Combination Therapies Comprising Implantable Attenuation Devices and Therapeutic Agents for Treating Conditions, and Related Systems and Methods of Use - Patent application

Abstract

Disclosed herein are devices, systems, and methods for the combined treatment of a condition with an implantable attenuation device and a therapeutic agent. A method for treating one or more effects of a condition, such as a neurological condition, includes providing to a patient an implantable attenuation device and at least one other therapy, such as a therapeutic agent, that treats the condition. The implantable attenuation device includes a flexible attenuation member and a mitigation substance and can be placed in juxtaposition with a blood vessel. The flexible attenuation member forms a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having a partially deformable portion. The mitigation substance is disposed within the partially deformable portion and moves longitudinally and / or radially within the partially deformable portion in response to pulsatile blood flow.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 63 / 235,506, filed August 20, 2021, entitled "COMBINATORIAL THERAPIES INCLUDING IMPLANTABLE DAMPING DEVICES AND THERAPEUTIC AGENTS FOR TREATING A CONDITION AND ASSOCIATED SYSTEMS AND METHODS OF USE," which is incorporated by reference in its entirety.

[0002] The present technology relates to combination therapies including an implantable attenuation device and a therapeutic agent for treating a condition (e.g., a neurodegenerative condition such as dementia), as well as related systems and methods of use. Specifically, the present technology is directed to combination therapies including an implantable attenuation device for positioning at, near, within, around, or in place of at least a portion of an artery, and one or more therapeutic agents (e.g., EDG receptor family modulators, MMP inhibitors, and senolytic agents) for treating a condition. [Background technology]

[0003] Any discussion of prior art throughout this specification should in no way be taken as an admission that such prior art is widely known or forms part of the common general knowledge in the art.

[0004] The heart supplies oxygenated blood to the body through a network of interconnected branching arteries that begin with the largest artery in the body, the aorta. As shown in the schematic diagram of the heart and selected arteries in FIG. 1A, the portion of the aorta closest to the heart is divided into three regions: the ascending aorta (where the aorta leaves the heart first and extends upwards), the aortic arch, and the descending aorta (where the aorta extends downwards). Three major arteries branch off from the aorta along the aortic arch: the brachiocephalic artery, the left common carotid artery, and the left subclavian artery. The brachiocephalic artery extends away from the aortic arch and then divides into the right common carotid artery, which supplies oxygenated blood to the head and neck, and the right subclavian artery, which supplies blood primarily to the right arm. The left common carotid artery extends away from the aortic arch and supplies the head and neck. The left subclavian artery extends away from the aortic arch and supplies blood primarily to the left arm. The right and left common carotid arteries then each branch into separate internal and external carotid arteries.

[0005] During the systolic phase of the heartbeat, contraction of the left ventricle forces blood into the ascending aorta, increasing pressure within the arteries (known as systolic pressure). The volume of blood ejected from the left ventricle creates a pressure wave, known as a pulse wave, which propagates through the arteries, propelling the blood. The pulse wave causes the arteries to dilate, as shown diagrammatically in FIG. 1B. As the left ventricle relaxes (the diastolic phase of the heartbeat), pressure within the arterial system decreases (known as diastolic pressure), causing the arteries to constrict.

[0006] The difference between systolic and diastolic blood pressure is the "pulse pressure", which is generally determined by, among other factors, the magnitude of the contractile force generated by the heart, heart rate, peripheral vascular resistance, and diastolic "runoff" (e.g., blood flow from arteries to veins with a pressure gradient). High-flow organs, such as the brain, are particularly sensitive to excessive pressure and flow pulsatility. To ensure relatively consistent flow to such sensitive organs, the walls of arterial vessels expand and contract in response to pressure waves to absorb some of the pulse wave energy. However, as the vasculature ages, the arterial walls become less elastic, causing an increase in pulse wave velocity and wave reflection through the arterial vasculature. Arterial stiffening impairs the ability of the carotid arteries and other large arteries to expand and dampen blood flow pulsations, resulting in increased systolic and pulse pressures. Thus, as arterial walls stiffen over time, the arteries transmit excess force to distal branches of the arterial vasculature.

[0007] Research suggests that consistently high systolic pressure, pulse pressure, and / or pressure change over time (dP / dt) increase the risk of dementia, such as vascular dementia (e.g., impaired blood supply to the brain or intracerebral hemorrhage). Without being bound by theory, it is believed that high pulse pressure may be an underlying cause or exacerbating factor of vascular dementia and age-related dementia (e.g., Alzheimer's disease). Thus, the progression of vascular dementia and age-related dementia (e.g., Alzheimer's disease) may also be influenced by loss of elasticity in arterial walls and the resulting stress on cerebral blood vessels. For example, Alzheimer's disease is commonly associated with the presence of senile plaques and tangles in the brain. Recent studies suggest that elevated pulse pressure, elevated systolic pressure, and / or increased rate of pressure change (dP / dt) over time may cause microbleeds in the brain that may contribute to senile plaques and tangles.

[0008] It is estimated that by 2050, at least 1 in 85 people worldwide will be living with Alzheimer's disease, with over 8 times as many showing preclinical symptoms. Additional disease-modifying therapies have been developed and are currently under development to prevent or delay the onset or progression of neurological conditions such as dementia. As of March 2020, there are 2272 clinical trials and / or other related trials underway for the treatment of Alzheimer's disease, one of several neurological conditions that are becoming increasingly common as the world's population ages. While the therapeutic agents being tested in these clinical trials may improve memory, behavior, cognition, and / or reduce the neuropsychiatric symptoms of Alzheimer's disease, there is a need for additional studies testing the efficacy, safety, and tolerability of these therapeutic agents, and / or the use of additional therapeutic agents. Thus, there is a need for improved devices, systems, and methods for treating vascular and / or age-related dementia. Summary of the Invention

[0009] According to a first aspect of the present invention there is provided a method for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising the steps of: A device for treating and / or preventing one or more effects of the condition, the device being configured to be placed in apposition to a blood vessel, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; providing a therapy in combination with the device to treat or delay one or more effects of the condition, the therapy being an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0010] According to a second aspect of the present invention there is provided a method for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising the steps of: A device for treating and / or preventing one or more effects of the condition, the device being configured to be placed in apposition to a blood vessel, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; providing a therapy in combination with the device to treat or delay one or more effects of the condition, the therapy being an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0011] According to a third aspect of the present invention there is provided a method for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising the steps of: providing a therapy for treating and / or preventing one or more effects of the condition to a subject in need thereof, the subject having previously been provided with a device that treats or delays one or more effects of the condition and that is placed in apposition to a blood vessel, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; Methods are provided wherein the therapy is an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0012] According to a fourth aspect of the present invention there is provided a system for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising: an effective amount of a therapy for treating and / or preventing one or more of the effects of the condition; and a device for treating and / or preventing one or more effects of the condition, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; Systems are provided wherein the therapy is an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0013] According to a fifth aspect of the present invention there is provided a system for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising: an effective amount of a therapy for treating and / or preventing one or more effects of the condition, the therapy being an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof; and a device for treating and / or preventing one or more effects of the condition, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions configured to move longitudinally and / or radially within the one or more at least partially deformable portions in response to pulsatile blood flow within the blood vessel; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; the effective amount of the therapy for treating and / or preventing one or more effects of the condition is delivered by one or more of the at least partially deformable portions of the device; A system is provided in which, upon at least partial deformation of the one or more at least partially deformable portions, the effective amount of a therapy for treating and / or preventing one or more effects of the condition is released from the device.

[0014] According to a sixth aspect of the invention there is provided a method for treating a patient having a condition comprising the steps of: (a) the patient has elevated pulse pressure or elevated pulse wave intensity / FCWI and a history of microbleeds, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, elevated reactive oxygen species, or a combination thereof; (i) obtaining or having been obtained information indicating that the patient has the elevated pulse pressure or the elevated pulse wave intensity / FCWI and has previously had symptoms of microbleeding, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating cytokine, increased reactive oxygen species, or a combination thereof, and / or has previously been diagnosed with microbleeding, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating cytokine, increased reactive oxygen species, or a combination thereof; and / or (ii) monitoring or having been monitored for symptoms of elevated pulse pressure and microhemorrhage, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating cytokine, elevated reactive oxygen species, or a combination thereof; (b) the patient has previously had symptoms of microbleeds, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated level of a circulating or CSF cytokine, increased reactive oxygen species, or a combination thereof; the patient has previously been diagnosed with microbleeds, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated level of a circulating cytokine, increased reactive oxygen species, or a combination thereof; and / or the patient has been monitored for symptoms of microbleeds, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated level of a circulating cytokine, increased reactive oxygen species, or a combination thereof; (i) providing to the patient an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof; (ii) providing a device for treating and / or preventing one or more effects of the condition, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions configured to move longitudinally and / or radially within the one or more at least partially deformable portions in response to pulsatile blood flow within the blood vessel; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; (c) providing the device to treat and / or prevent one or more effects of the condition if the patient has not previously been diagnosed with microhemorrhage, APOE4 expression, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, increased reactive oxygen species, or a combination thereof, if the patient has not previously been diagnosed with microhemorrhage, APOE4 expression, blood-brain barrier dysfunction or permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, increased reactive oxygen species, or a combination thereof.

[0015] It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0016] Unless the context clearly requires otherwise, throughout this specification and the claims, the words "comprise", "comprising", and the like, are to be construed in their inclusive sense, i.e., "including, but not limited to", rather than in their exclusive or exhaustive sense. [Brief description of the drawings]

[0017] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure.

[0018] [Figure 1A] FIG. 1A is a schematic diagram of the human heart and a portion of the arterial system near the heart.

[0019] [Figure 1B] FIG. 1B is a schematic diagram of a pulse wave propagating along a blood vessel.

[0020] [Figure 2A] FIG. 2A is a front view of an attenuation device in accordance with the present technology shown in a deployed, relaxed state.

[0021] [Figure 2B] FIG. 2B is a front cross-sectional view of the attenuation device shown in FIG. 2A.

[0022] [Figure 2C] FIG. 2C is a front cross-sectional view of the attenuation device shown in FIG. 2A shown in a deployed state positioned within a blood vessel.

[0023] [Figure 2D] FIG. 2D is a cross-sectional front view of another embodiment of an attenuation device in accordance with the present technology shown in a deployed, relaxed state.

[0024] [Figure 2E] 2E-2G are cross-sectional front views of several embodiments of damping members in accordance with the present technology, all shown in a deployed, relaxed state. [Figure 2F] 2E-2G are cross-sectional front views of several embodiments of damping members in accordance with the present technology, all shown in a deployed, relaxed state. [Figure 2G] 2E-2G are cross-sectional front views of several embodiments of damping members in accordance with the present technology, all shown in a deployed, relaxed state.

[0025] [Figure 3A] FIG. 3A is a front cross-sectional view of another embodiment of an attenuation device in accordance with the present technology shown in a deployed, relaxed state.

[0026] [Figure 3B] 3B-3D are cross-sectional front views of several embodiments of damping members in accordance with the present technology, all shown in a deployed, relaxed state. [Figure 3C] 3B-3D are cross-sectional front views of several embodiments of damping members in accordance with the present technology, all shown in a deployed, relaxed state. [Figure 3D] 3B-3D are cross-sectional front views of several embodiments of damping members in accordance with the present technology, all shown in a deployed, relaxed state.

[0027] [Figure 4A] FIG. 4A is a front view of an attenuation device in accordance with another embodiment of the present technology shown in a deployed, relaxed state.

[0028] [Figure 4B] FIG. 4B is a front cross-sectional view of the attenuation device shown in FIG. 4A.

[0029] [Figure 4C] FIG. 4C is a front cross-sectional view of the attenuation device shown in FIG. 4A shown in a deployed state positioned within a blood vessel.

[0030] [Figure 4D] FIG. 4D is a cross-sectional front view of a portion of a damping member in accordance with the present technology, showing deformation of the damping member in response to a pulse wave (dashed lines).

[0031] [Figure 4E] FIG. 4E is a cross-sectional front view of a portion of another damping member in accordance with the present technology, illustrating deformation of the damping member in response to a pulse wave (dashed lines).

[0032] [Diagram 5] 5-7 are front cross-sectional views of several embodiments of attenuation devices in accordance with the present technology. [Figure 6] 5-7 are front cross-sectional views of several embodiments of attenuation devices in accordance with the present technology. [Figure 7] 5-7 are front cross-sectional views of several embodiments of attenuation devices in accordance with the present technology.

[0033] [Figure 8A] 8A-8E show a method of delivering an attenuation device according to the present technology to an artery. [Figure 8B] 8A-8E show a method of delivering an attenuation device according to the present technology to an artery. [Figure 8C] 8A-8E show a method of delivering an attenuation device according to the present technology to an artery. [Figure 8D] 8A-8E show a method of delivering an attenuation device according to the present technology to an artery. [Figure 8E] 8A-8E show a method of delivering an attenuation device according to the present technology to an artery.

[0034] [Figure 9A] 9A-9F are schematic cross-sectional views of several embodiments of damping members according to the present technology. [Figure 9B] 9A-9F are schematic cross-sectional views of several embodiments of damping members according to the present technology. [Figure 9C] 9A-9F are schematic cross-sectional views of several embodiments of damping members according to the present technology. [Figure 9D] 9A-9F are schematic cross-sectional views of several embodiments of damping members according to the present technology. [Figure 9E] 9A-9F are schematic cross-sectional views of several embodiments of damping members according to the present technology. [Figure 9F] 9A-9F are schematic cross-sectional views of several embodiments of damping members according to the present technology.

[0035] [Figure 10]10 and 11 are front cross-sectional views of an embodiment of an attenuation device in accordance with the present technology shown positioned at or near a resected blood vessel. [Figure 11] 10 and 11 are front cross-sectional views of an embodiment of an attenuation device in accordance with the present technology shown positioned at or near a resected blood vessel.

[0036] [Figure 12A] FIG. 12A is a front view of a helical attenuation device in accordance with the present technology shown positioned about a blood vessel in a deployed, relaxed state.

[0037] [Figure 12B] FIG. 12B is a cross-sectional view of the attenuation device of FIG. 12A (taken along line 12B-12B of FIG. 12A) shown positioned about a blood vessel as a pulse pressure wave travels through the vessel.

[0038] [Figure 13] 13 and 14 show different embodiments of a wrapped attenuation device in accordance with the present technology, each shown positioned around a blood vessel. [Figure 14] 13 and 14 show different embodiments of a wrapped attenuation device in accordance with the present technology, each shown positioned around a blood vessel.

[0039] [Figure 15] FIG. 15 is a cross-sectional view of another embodiment of an attenuation device in accordance with the present technology.

[0040] [Figure 16A] FIG. 16A is a perspective view of another embodiment of an attenuation device in accordance with the present technology.

[0041] [Figure 16B] FIG. 16B is a cross-sectional view of the attenuation device shown in FIG. 16A taken along line 16B-16B.

[0042] [Figure 17A] FIG. 17A is a perspective view of another embodiment of an attenuation device in accordance with the present technology.

[0043] [Figure 17B] FIG. 17B is a cross-sectional view of the attenuation device shown in FIG. 17A.

[0044] [Figure 18A] FIG. 18A is a perspective view of another embodiment of an attenuation device in accordance with the present technology.

[0045] [Figure 18B] FIG. 18B is a front view of the attenuation device shown in FIG. 18A shown in a deployed state positioned about a blood vessel.

[0046] [Figure 19A] FIG. 19A is a perspective view of an attenuation device in accordance with another embodiment of the present technology shown in an unwrapped state.

[0047] [Figure 19B] FIG. 19B is a top view of the attenuation device shown in FIG. 19A, shown in an unwrapped state.

[0048] [Figure 20] FIG. 20 is a flow diagram illustrating a method according to the present technology.

[0049] [Figure 21] 21 is a graph showing body weight at weekly intervals from one week before TAC surgery (W-1) to six weeks after TAC surgery (W6), according to some embodiments. Data are mean ± standard error of the mean (*: p<0.05 compared to simple sutures, by unpaired t-test).

[0050] [Figure 22A] FIG. 22A is a graph showing echocardiogram data assessing peak velocity in mice receiving simple sutures, according to some embodiments.

[0051] [Figure 22B] FIG. 22B is a graph showing echocardiogram data assessing peak velocity in mice receiving absorbable sutures, according to some embodiments.

[0052] [Diagram 23] 23 is a dot plot showing % change in the Y-maze comparing mice with absorbable sutures without treatment to mice with plain sutures, according to some embodiments. The number of alternations in the three arms of the Y-maze was measured by the following formula: % Alternations = (Total Alternations / (Total Entries-2) x 100). The absorbable suture group had a mean % change of 61.63 (SD = 13.25, standard error of the mean (SEM) = 3.675, n = 13) and the plain suture group had a mean % change of 68.39 (SD = 10.44, standard error of the mean = 2.395, n = 19).

[0053] [Figure 24] 24 is a dot plot showing % change in a Y-maze comparing mice with treated or untreated absorbable sutures to mice with plain sutures, according to some embodiments. The number of alternations in the three arms of the Y-maze was measured by the following formula: % Alternations = (Total Alternations / (Total Entries-2) x 100). The untreated absorbable suture group had a mean % change of 61.907 (standard error of the mean = 7.246, n = 6) and the untreated simple suture group had a mean % change of 65.130 (standard error of the mean = 4.682, n = 7). The treated absorbable suture group had a mean % change of 61.396 (standard error of the mean = 3.556, n = 7) and the treated simple suture group had a mean % change of 70.296 (standard error of the mean = 2.644, n = 12).

[0054] [Diagram 25] FIG. 25 is a schematic diagram illustrating a treatment protocol according to some embodiments.

[0055] [Figure 26A] FIG. 26A is a dot plot showing Evans blue data in the right hemisphere of mice treated with fingolimod.

[0056] [Figure 26B] FIG. 26B is a normal QQ plot showing the results of testing the normality and log-normality of the Evans Blue data.

[0057] [Figure 27] FIG. 27 is a dot plot showing region-of-interest (ROI) Evans blue data from individual mice (*p<0.05).

[0058] [Figure 28] FIG. 28 is a dot plot showing region of interest (ROI) Evans blue data from individual mice.

[0059] [Figure 29A] FIG. 29A is a graph showing peak velocity based on Evans Blue data in untreated (placebo) mice.

[0060] [Figure 29B] FIG. 29B is a graph showing peak velocity based on Evans Blue data in mice treated with fingolimod.

[0061] [Figure 30A]FIG. 30A is a bar graph showing expression levels of S1P1 measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated or untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)). Abbreviations in FIG. 30A-FIG. 38B: RH, right (ipsilateral) hemisphere, n=3; LH, left (contralateral) hemisphere (n=3 mice in each group); no TT=no treatment (vehicle); TT=treatment (fingolimod, 0.01 mg / day in drinking water for the last 2 weeks, i.e., 0.3 mg / kg / day).

[0062] [Figure 30B] FIG. 30B is a bar graph showing expression levels of S1P1 measured by RT-PCR in the microvascular fraction of whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0063] [Figure 31A] FIG. 31A is a bar graph showing the expression levels of S1P3 measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated and untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0064] [Figure 31B] FIG. 31B is a bar graph showing expression levels of S1P3 measured by RT-PCR in the microvascular fraction of whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0065] [Figure 32A] FIG. 32A is a bar graph showing expression levels of B2M measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated or untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0066] [Figure 32B] FIG. 32B is a bar graph showing expression levels of B2M measured by RT-PCR in the microvascular fraction of whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0067] [Figure 33A] FIG. 33A is a bar graph showing expression levels of CERS4 measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated and untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0068] [Figure 33B] FIG. 33B is a bar graph showing expression levels of CERS4 measured by RT-PCR in the microvascular fraction of whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0069] [Figure 34A] FIG. 34A is a bar graph showing the expression levels of CERS2 measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated or untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0070] [Figure 34B] FIG. 34B is a bar graph showing expression levels of CERS2 measured by RT-PCR in the microvascular fraction of the whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0071] [Figure 35A]FIG. 35A is a bar graph showing the expression levels of Claudin 5 measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated or untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0072] [Figure 35B] FIG. 35B is a bar graph showing expression levels of Claudin 5 measured by RT-PCR in the microvascular fraction of the whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0073] [Figure 36A] FIG. 36A is a bar graph showing the expression levels of ICAM measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated and untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0074] [Figure 36B] FIG. 36B is a bar graph showing expression levels of ICAM measured by RT-PCR in the microvascular fraction of whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0075] [Figure 37A] FIG. 37A is a bar graph showing the expression levels of VCAM measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated and untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0076] [Figure 37B] FIG. 37B is a bar graph showing expression levels of VCAM measured by RT-PCR in the microvascular fraction of the whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)).

[0077] [Figure 38A] FIG. 38A is a bar graph showing expression levels of MMP9 measured by RT-PCR in the ipsilateral and contralateral hemispheres of the brain of three treated or untreated mice (paired statistical analysis, left hemisphere (LH) vs. right hemisphere (RH), unpaired t-test (no TT vs. TT)).

[0078] [Figure 38B] FIG. 38B is a bar graph showing expression levels of MMP9 measured by RT-PCR in the microvascular fraction of whole brain (untreated vs. treated, n=5 / group, unpaired t-test (no TT vs. TT)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] The present technology is directed to implantable attenuation devices and combination therapies including therapeutic agents (e.g., EDG receptor family modulators, MMP inhibitors, and senolytic agents) for treating and / or preventing progression of conditions, including neurological conditions such as dementia (e.g., vascular dementia and age-related dementia), as well as related systems and methods of use. Some embodiments of the present technology are directed to combination devices and therapies including, for example, an attenuation device having an anchoring member and a flexible compliant attenuation member having an outer surface and an inner surface defining a lumen configured to direct blood flow. The inner surface is configured such that the cross-sectional dimension of the lumen varies. For example, the outer surface and the inner surface can be separated from each other by a distance that varies along the length of the attenuation member. The attenuation member can further include a first end, a second end opposite the first end, and an attenuation region between the first end and the second end. The distance between the outer surface and the inner surface of the attenuation member can be greater at the attenuation region than at either the first end or the second end. As blood flows through the damping member during systole, the damping member absorbs a portion of the blood's pulsating energy to reduce the magnitude of the pulse pressure transmitted to the portion of the blood vessel distal to the attenuation device. Additional embodiments of the present technology are directed to combination devices and therapies that include therapeutic agents (e.g., EDG receptor family modulators, MMP inhibitors, and senolytic agents) that have been developed or are currently being developed to treat or otherwise delay the effects of neurological conditions. These therapeutic agents, as well as other therapeutic agents derived from and / or otherwise based on these therapeutic agents, are included in embodiments of the present technology. Specific details of some embodiments of the present technology are described below with reference to Figures 2A-20.

[0080] With respect to the terms "distal" and "proximal" herein, unless otherwise specified, these terms can refer to the relative location of the attenuation device and / or portions of an associated delivery device relative to an operator, the direction of blood flow through a blood vessel, and / or a location within the vasculature. For example, when referring to a delivery catheter suitable for delivery and positioning the various attenuation devices described herein, "proximal" refers to a location closer to the operator of the device or an incision into the vasculature, and "distal" refers to a location more distal from the operator of the device or further from an incision (e.g., the end of the catheter) along the vasculature.

[0081] As used herein, "arteries" and "arteries supplying blood to the brain" include any arterial vessel (or portion thereof) that provides oxygenated blood to the brain. For example, "arteries" or "arteries supplying blood to the brain" can include the ascending aorta, the aortic arch, the brachiocephalic trunk, the right common carotid artery, the left common carotid artery, the left internal carotid artery and the right internal carotid artery, the left external carotid artery and the right external carotid artery, and / or any branches and / or extensions of any of the above arterial vessels.

[0082] As used herein, the terms "therapeutic agent", "drug", "therapy" and "therapies" are used interchangeably herein and refer to drugs and / or therapies described herein, including EDG receptor family modulators, MMP inhibitors, and / or senolytic agents. Drugs and therapies may be composed of a wide variety of substances, including, but not limited to, sugars (or other small molecules), synthetic chemicals, proteins or peptides, nucleic acids, complex combinations of these substances, or may be living organisms such as cells or tissues. Drugs and therapies include a wide variety of products and treatments that may be isolated from or otherwise obtained from natural sources (e.g., human, animal, plant, microbial) using recombinant, synthetic, or other biotechnology methods and techniques. For example, synthetically produced peptides or other natural molecules may be considered drugs according to the present disclosure.

[0083] The terms "recipient," "individual," "subject," "host," and "patient" are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired, particularly humans. For purposes of treatment, "mammal" refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, etc. Preferably, the mammal is a human.

[0084] With respect to the term "neurological condition" herein, unless otherwise specified, the term refers to conditions, disorders, and / or diseases of the brain, spine, and the nerves connecting the brain and spine. Neurological conditions include, but are not limited to, dementia (e.g., vascular dementia, frontotemporal dementia, Lewy body dementia), Alzheimer's disease, Huntington's disease, cognitive impairment, Parkinson's disease, neuralgia, tumors, cancer, stroke, aneurysm, epilepsy, headache, and / or migraine.

[0085] As used herein, "subject in need thereof" refers to a mammalian subject, preferably a human, who has been diagnosed with a neurological condition, is suspected of having a neurological condition, and / or exhibits one or more symptoms or risk factors associated with a neurological condition.

[0086] The terms "treat" and "treatment" in the context of a given condition, disease, or disorder are used interchangeably and include, but are not limited to, inhibiting the disease or disorder, e.g., arresting the onset or rate of onset of the condition, disease, or disorder; alleviating the condition, disease, or disorder, e.g., causing regression of the condition, disease, or disorder; or alleviating a condition caused by or resulting from the disease or disorder, e.g., inhibiting, alleviating, preventing, or causing regression of at least one of the symptoms of the disease or disorder.

[0087] The terms "prevent" and "prevention" in the context of a given condition, disease, or disorder are used interchangeably and include, but are not limited to, preventing or delaying the onset of its development if none would have occurred; preventing or delaying the onset of the condition, disease, or disorder in a subject who may be predisposed to the condition, disease, or disorder, but has not yet been diagnosed as having the condition, disease, or disorder; and / or preventing or delaying further onset of the condition, disease, or disorder if already present.

[0088] As used herein, "route" in the context of administration of one or more therapies, such as a therapeutic agent (e.g., a drug), refers to the route by which the therapeutic agent is delivered to a subject, e.g., the subject's body. Therapeutic routes of administration include enteral and parenteral routes of administration. Enteral administration includes oral, rectal, intestinal, and / or enema. Parenteral includes topical, transdermal, epidural, intracerebral, intraventricular, epicutaneous, sublingual, sublabial, buccal, inhalation (e.g., nasal), intravenous, intraarticular, intracardiac, intradermal, intramuscular, intraocular, intraosseous injection, intraperitoneal, intrathecal, intravitreal, subcutaneous, perivascular, implantation, vaginal, auricular, and / or transmucosal.

[0089] Any concentration range, percentage range, ratio range, or integer range herein should be understood to include any integer value in the recited range, and fractions thereof (such as tenths and hundredths of integers), if appropriate, unless otherwise indicated. Any numerical range recited herein should also be understood to include any integer in the recited range, unless otherwise indicated. As used herein, the term "about" means ±20% of the indicated range, value, or structure, unless otherwise indicated. It should be understood that the terms "a" and "an" used herein refer to "one or more" of the recited range. Words using the singular or plural also include the plural or singular, respectively. The use of the word "or" in reference to a list of two or more items includes the following interpretations of that word: any of the items in the list, all of the items in the list, and any combination of the items in the list. Furthermore, the phrase "at least one of A, B, and C, etc." is intended in a sense that one of ordinary skill in the art would understand to be conventional (e.g., "a system having at least one of A, B, and C" would include, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B and C together, etc.). In instances where a convention similar to "at least one of A, B, or C, etc." is used, generally such configurations are intended in a sense that one of ordinary skill in the art would understand to be conventional (e.g., "a system having at least one of A, B, or C" would include, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B and C together, etc.). As used herein, the terms "include," "have," and "comprise" are used interchangeably and these terms and variations thereof are intended to be construed as open-ended. In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed embodiments.

[0090] The present invention has been described with respect to specific embodiments found or proposed by the inventors to include preferred modes for carrying out the invention. In light of this disclosure, it will be understood by those skilled in the art that numerous modifications and variations can be made to the specific embodiments exemplified without departing from the intended scope of the invention. For example, due to codon redundancy, changes can be made to the underlying DNA sequence without affecting the protein sequence. Furthermore, due to biological functional equivalence considerations, changes can be made to the protein structure without affecting the biological action in terms of type or amount. All such modifications are intended to be included within the scope of the appended claims.

[0091] While the present invention can be embodied in various forms, the following description of some embodiments is made with the understanding that the present disclosure should be considered as an example of the present invention and is not intended to limit the present invention to the specific embodiments shown. Headings are provided for convenience only and should not be construed as limiting the present invention in any manner. An embodiment illustrated under any heading can be combined with an embodiment illustrated under any other heading.

[0092] I. SELECTED ENDOVASCULAR EMBODIMENTS OF THE ATTENUATION DEVICE 2A and 2B are front and front cross-sectional views, respectively, of an attenuation device 100 configured in accordance with the present technology shown in an expanded or deployed state. FIG. 2C is a front view of the attenuation device 100 in a deployed state positioned within a carotid artery (CA) (e.g., left or right carotid artery). Referring together to FIGS. 2A-2C, the attenuation device 100 includes a flexible viscoelastic damping member 102 (e.g., a cushioning member) and an anchoring member 104 (individually identified as first anchoring member 104a and second anchoring member 104b, respectively). The damping member 102 includes an undulating or hourglass shaped sidewall having an outer surface 115 and an inner surface 113 (FIGS. 2B and 2C) that defines a lumen 114 configured to receive blood flow therethrough. The outer surface 115 is spaced a distance t from the inner surface 113 (FIG. 2B). The damping member 102 has a length L, a first end 106, a second end 108 opposite the first end 106 along the length L, and a damping region 120 between the first end 106 and the second end 108. In the embodiment shown in FIGS. 2A-2C, the distance t between the outer surface 115 and the inner surface 113 varies along the length L of the damping member 102 when in a deployed, relaxed state. In some embodiments, the distance t between the outer surface 115 and the inner surface 113 may be greater, on average, at the damping region 120 than at either the first end 106 or the second end 108. In other embodiments, the damping member 102 may have other suitable shapes (e.g., FIGS. 2E-2G), sizes, and / or configurations. For example, as shown in FIG. 2D, the distance t between the outer surface 115 and the inner surface 113 may be substantially constant along the length of the damping member 102 and / or damping region 120 when the damping member 102 is in a deployed, relaxed state.

[0093] The damping member 102 shown in FIGS. 2A-2C is a solid piece of material molded, extruded, or otherwise formed into a desired shape. The damping member 102 may be made from a biocompatible compliant viscoelastic material configured to deform in response to local fluid pressure in the artery. As the damping member 102 deforms, it absorbs a portion of the pulse pressure. The damping member 102 may be made from a biocompatible synthetic elastomer, such as, for example, silicone rubber (VMQ), Tufel I and Tufel III elastomers (GE Advanced Materials, Pittsfield, MA), Sorbothane® (Sorbothane, Incorporated, Kent, OH). The damping member 102 may be flexible and elastic such that an inner diameter (ID) of the damping member 102 at the damping region 120 increases as the systolic pressure wave propagates through the damping region 120. For example, a systolic pressure wave may push the inner surface 113 radially outwardly, thus also deforming a portion of the outer surface 115 radially outwardly. Additionally, the damping member 102 may be compressible as needed, such that as a systolic pressure wave engages the damping region 120, the distance t between the inner surface 115 and the outer surface 113 decreases, further opening the inner diameter ID of the damping region 120. For example, a systolic pressure wave may push the inner surface 113 radially outwardly, while the contour of the outer surface 115 remains largely unaffected.

[0094] In the embodiment shown in FIGS. 2A-2C, the anchoring members 104a-b each comprise a generally cylindrical structure configured to expand from a low-profile state to a deployed state in apposition with the vessel wall. The anchoring members 104a-b can each be a stent formed from a superelastic material (e.g., Nitinol) or a laser-cut metal such as stainless steel. All or a portion of each anchoring member can include a radiopaque coating to improve visualization of the device during delivery, and / or the anchoring members may include one or more radiopaque markers. In other embodiments, the individual anchoring members 104a-104b can comprise a mesh or woven (e.g., braided) structure in addition to or in lieu of a laser-cut stent. For example, the individual anchoring members 104a-104b can include a tube or braided mesh formed from a plurality of flexible wires or filaments arranged in a diamond pattern or other configuration. In some embodiments, all or a portion of one or both of the anchoring members 104a-104b can be covered with a graft material (such as Dacron) to facilitate sealing with the vessel wall. Additionally, all or a portion of one or both of the anchoring members can include one or more biomaterials.

[0095] In the embodiment shown in FIG. 2A-2B, the anchoring members 104a-104b are positioned around the damping member 102 at the first end 106 and the second end 108, respectively. Thus, in this embodiment, the outer diameter (OD) of the damping member 102 is less than the inner diameter of the anchoring members 104a-104b. Also, in the embodiment shown in FIG. 2A-2B, the anchoring members 104a-104b are positioned around the damping member 102 only at the first end 106 and the second end 108, respectively. Thus, in some embodiments of the present technology, the damping region 120 of the damping member 120 is not surrounded by a stent-like structure or braided material. In other embodiments, the anchoring members 104 and the damping member 102 may have other suitable configurations. For example, the anchoring members 104a-104b may be positioned elsewhere along the length L of the damping member 102 rather than the entire length of the damping member 102. Also, in some embodiments, all or a portion of one or both of the anchoring members 104a-104b may be positioned radially outward of all or a portion of the damping member 102. Although the attenuation device 100 shown in Figures 2A-2B includes two anchoring members 104a-104b, in other embodiments, the attenuation device 100 can have more or fewer anchoring members (e.g., one anchoring member, three anchoring members, four anchoring members, etc.).

[0096] In some embodiments, a biocompatible gel or liquid can be positioned between the wall of the artery A and the outer surface 115 of the damping member 102 to prevent blood from entering the gap defined between the first fixation member 104a, the second fixation member 104b, the damping member 102, and the inner wall of the artery CA. Alternatively, air or another gas can be positioned between the inner wall of the carotid artery CA and the damping member 102 to prevent blood from entering the gap.

[0097] FIG. 3A is a front cross-sectional view of another embodiment of an attenuation device 100' according to the present technology. The embodiment of the attenuation device 100' shown in FIG. 3A is similar to the embodiment of the attenuation device 100 shown in FIG. 2A-2C, and in FIG. 2A-2C and FIG. 3A, like reference numbers refer to like components. As shown in FIG. 3A, the attenuation device 100' includes an inner damping member 102 and an outer layer 130 surrounding the damping member 102. The outer layer 130 has an outer surface 131, and in the embodiment shown in FIG. 3A, a first fastening member 104a and a second fastening member 104b are attached to the outer surface 131. At least along the damping region 120, the outer layer 130 is spaced from the outer surface 115 of the damping member 102 to form a chamber 132. The chamber 132 can be at least partially filled with a fluid, such as a gas, liquid, or gel. The device 100' has a length L and a distance d between the outer surface 131 of the outer layer 130 and the inner surface 113 of the damping member 102. Along the damping region 120, the distance d between the outer surface 131 and the inner surface 113 increases radially when the damping member 102 is in a deployed, relaxed state, and then decreases. On average, the distance d between the outer surface 131 and the inner surface 113 of the damping member 102 is greater at the damping region 120 than at either the first end 106 or the second end 108. As a result, the inner diameter ID of the lumen 114 varies along the length L. For example, the outer surface 131 and / or the outer layer 130 can be generally cylindrical in an unbiased state, and the inner surface 113 and / or the damping member 102 can have an undulating or hourglass shape. In other embodiments, outer surface 131 and / or outer layer 130 can have other suitable shapes, and inner surface 113 and / or damping member 102 can have other suitable shapes (Figures 3B-3D).

[0098] In some embodiments, instead of the attenuation device 100' having a separate outer layer 130, the damping member 102 can be molded, formed, or otherwise extruded to seal a cavity. For example, as shown in Figures 3B-3D, the damping member 102' can include an inner layer 116, an outer layer 118, and a cavity 119 therebetween. The cavity 119 can be at least partially filled with a fluid, such as a gas, liquid, or gel.

[0099] 4A and 4B are front and front cross-sectional views, respectively, of another embodiment of an attenuation device 200 configured in accordance with the present technology, shown in an expanded or deployed state. FIG. 4C is a front cross-sectional view of the attenuation device 200 in a deployed state positioned within a carotid artery (e.g., a left or right carotid artery). Referring together to FIGS. 4A-4C, the attenuation device 200 includes a flexible viscoelastic damping member 202 (e.g., a cushioning member) and an anchoring member 204 (individually identified as a first anchoring member 204a and a second anchoring member 204b, respectively). As shown in FIGS. 4B and 4C, the damping member 202 includes a generally tubular sidewall having a cylindrical outer surface 210 and an inner surface 212 defining a lumen 214 configured to receive blood flow therethrough. The outer surface 210 is spaced a distance t from the inner surface 212 (FIG. 4B). The damping member 202 has a length L, a first end 206, a second end 208 opposite the first end 206 along the length L, and a damping region 220 between the first end 206 and the second end 208. Along the damping region 220, a distance t between the outer surface 210 and the inner surface 212 increases radially when the damping member 202 is in a deployed, relaxed state, and then decreases. On average, the distance t between the outer surface 210 and the inner surface 212 of the damping member 202 is greater at the damping region 220 than at either the first end 206 or the second end 208. As a result, an inner diameter ID of the damping member 202 varies along its length L relative to an outer diameter OD of the damping member 202. For example, the outer surface 210 can be generally cylindrical in an unbiased state, and the inner surface 212 can have an undulating or hourglass shape. As described in more detail below with respect to Figures 9A-9F, the damping member 202 can have other suitable shapes, sizes, and / or configurations.

[0100] The damping member 202 shown in FIGS. 4A-4C is a solid piece of material molded, extruded, or otherwise formed into a desired shape. The damping member 202 can be made from a biocompatible compliant viscoelastic material configured to deform in response to local fluid pressure in the artery. As the damping member 202 deforms, it absorbs a portion of the pulse pressure. The damping member 202 can be made from a biocompatible synthetic elastomer, such as, for example, silicone rubber (VMQ), Tufel I and Tufel III elastomers (GE Advanced Materials, Pittsfield, MA), Sorbothane® (Sorbothane, Incorporated, Kent, OH). The damping member 202 can be flexible and elastic such that an inner diameter ID of the damping member 202 at the damping region 220 increases as a systolic pressure wave P (FIG. 4D) propagates through the damping region 220. For example, as shown diagrammatically in the isolated cross-sectional view of a portion of the damping member 202 before and during deformation (damping member 202', shown in dashed lines) in FIG. 4D, the systolic pressure wave P may push the inner surface 212' radially outward, thus deforming a portion of the outer surface 210' radially outward as well. In addition, the damping member 202 may be compressible, if desired, such that as the systolic pressure wave P engages the damping region 220, the distance t between the inner surface 210 and the outer surface 212 decreases, further opening the inner diameter ID of the damping region 220. For example, as shown diagrammatically in the isolated cross-sectional view of a portion of the damping member 202 before and during deformation (damping member 202', shown in dashed lines) in FIG. 4E, the systolic pressure wave P may push the inner surface 212' radially outward, while the contour of the outer surface 210' remains largely unaffected.

[0101] In the embodiment shown in FIGS. 4A-4C, the anchoring members 204a-b each comprise a generally cylindrical structure configured to expand from a low-profile state to a deployed state in apposition with the vessel wall. The anchoring members 204a-b can each be a stent formed from a superelastic material (e.g., Nitinol) or a laser-cut metal such as stainless steel. All or a portion of each anchoring member can include a radiopaque coating to improve visualization of the device during delivery, and / or the anchoring members may include one or more radiopaque markers. In other embodiments, the individual anchoring members 204a-204b can comprise a mesh or woven (e.g., braided) structure in addition to or in lieu of a laser-cut stent. For example, the individual anchoring members 204a-204b can include a tube or braided mesh formed from a plurality of flexible wires or filaments arranged in a diamond pattern or other configuration. In some embodiments, all or a portion of one or both of the anchoring members 204a-204b may be covered with a graft material (such as Dacron) to promote a seal with the vessel wall.

[0102] In the embodiment shown in FIG. 4A-B, the anchoring members 204a-b are positioned around the damping member 202 at the first end 206 and the second end 208, respectively. Thus, in this embodiment, the outer diameter OD (FIG. 4A) of the damping member 202 is less than the inner diameter of the anchoring members 204a-b. Also, in the embodiment shown in FIG. 4A-B, the anchoring members 204a-b are positioned around the damping member 202 only at the first end 206 and the second end 208, respectively. Thus, in some embodiments of the present technology, the damping region 220 of the damping member 220 is not surrounded by a stent-like structure or braided material. In other embodiments, the anchoring members 204a-b and the damping member 202 may have other suitable configurations. For example, the anchoring members 204a-b may be positioned elsewhere along the length L of the damping member 202 rather than the entire length of the damping member 202. Also, in some embodiments, all or a portion of one or both anchoring members 204a-204b may be positioned radially outward from all or a portion of damping member 202. Although attenuation device 200 shown in Figures 4A-4B includes two anchoring members 204a-204b, in other embodiments, attenuation device 200 can have more or fewer anchoring members (e.g., one anchoring member, three anchoring members, four anchoring members, etc.).

[0103] In some embodiments, one or both of the anchoring members 204a-204b can optionally include one or more anchoring elements 205 (FIG. 4B) configured to engage the vessel wall. The anchoring elements 205 can include, for example, one or more hooks or barbs that, in a deployed state, extend outwardly away from the corresponding frame of the anchoring members 204a-204b to penetrate the vessel wall at the treatment site. In these and other embodiments, one or more of the anchoring elements can be atraumatic. Additionally, with reference to the attenuation device 200A shown in FIG. 5, in certain embodiments, the attenuation device 200 may not include a stent-type or braided-type anchoring member, but rather, the frame of the anchoring member 204 can be one or more expandable rings 230. For example, in some embodiments, the attenuation device 200 can include two rings 230, each attached to a respective end 206 and end 208, and multiple anchoring elements 205 can extend outwardly from the rings 230. In still other embodiments, such as the attenuation device 200B shown in FIG. 6, the anchoring member 204 can be an integral part of the ends 206, 208, such as the thick walled portions 240a-240b, of the damping member 202 that extend radially outward from the outer wall of the attenuation region 220, instead of a separate metal or polymer component. In this embodiment, the anchoring elements 205 can extend outward from the integral anchoring members 240a-240b at the first end 206 and the second end 208 of the damping member 202. When the attenuation device 200 is in the deployed state, the anchoring elements 205 extend outward from the outer surface of the damping member 202 to engage vessel wall tissue. In still other embodiments, the anchoring elements 205 can extend outward from the outer surface 210 of the damping member 202, as shown in the attenuation device 200C of FIG. 7.

[0104] Figures 8A-8E illustrate a method for positioning an attenuation device of the present disclosure at a treatment location within an artery A (such as the left common carotid artery and / or the right common carotid artery CA). Figures 8B-8E illustrate the attenuation device 200 shown in Figures 4A and 4B, however, the method and system described with respect to Figures 8A-8E may be utilized with any of the attenuation devices 100, 100', 200, 200A, 200B, and 200C described with respect to Figures 2A-7 and 9A-9F.

[0105] As shown in FIG. 8A, the guidewire 602 can be first advanced within a blood vessel from an access site, such as the femoral or radial artery, to enter a treatment site. The guide catheter 604 can then be advanced along the guidewire 602 until at least a distal portion of the guide catheter 604 is positioned at the treatment site. In these and other embodiments, rapid exchange techniques may be utilized. In some embodiments, the guide catheter 604 may have a pre-shaped or steerable distal end to direct the guide catheter 604 through one or more bends in the vasculature. For example, the guide catheter 604 shown in FIGS. 8A-8E has a curved distal end configured to navigate through the ascending aorta (AA) and direct the guide catheter 604 into the artery A with preferential bends or turns in the left common carotid artery A and / or right common carotid artery A.

[0106] Image guidance, such as computed tomography (CT), fluoroscopy, angiography, intravascular ultrasound (IVUS), optical coherence tomography (OCT), or another suitable guidance modality, or a combination thereof, can be used to assist the clinician in positioning and manipulating the attenuation device 200. For example, a fluoroscopy system (including, for example, a flat panel detector, X-ray, or c-arm) can be rotated to precisely visualize and identify the target treatment site. In other embodiments, the treatment site can be determined using IVUS, OCT, and / or other suitable image mapping modalities, which can correlate the target treatment site with identifiable anatomical structures (e.g., spinal features) and / or radiopaque rulers (e.g., positioned below or above the patient) prior to delivery of the attenuation device 200. Further, in some embodiments, image guidance components (e.g., IVUS, OCT) can be integrated with and / or run in parallel with the delivery catheter to provide image guidance during positioning of the attenuation device 200.

[0107] Once the guide catheter 604 is positioned at the treatment site, the guidewire 602 can be withdrawn. As shown in FIG. 8B and FIG. 8C, a delivery assembly 610 carrying the attenuation device 200 can then be advanced distally through the guide catheter 604 to the treatment site. In some embodiments, the delivery assembly 610 includes an elongate shaft 612 having an atraumatic distal tip 614 (FIG. 8B) and an expandable member 616 (e.g., an inflatable balloon, an expandable cage, etc.) positioned about a distal portion of the elongate shaft 612. The attenuation device 200 can be positioned about the expandable member 616. As shown in FIG. 8D, expansion or inflation of the expandable member 616 urges at least a portion of the attenuation device 200 radially outward into contact with the arterial wall. In some embodiments, the delivery assembly 610 can include an expandable distal member for deploying a distal portion of the attenuation device 200 and an expandable proximal member for deploying a proximal portion of the attenuation device 200. In other embodiments, the entire length of the attenuation device 200 may be expanded simultaneously by deploying one or more expandable members.

[0108] In some procedures, a clinician may wish to stretch or elongate the attenuation device 200 prior to deploying the proximal second anchor member 204b against the arterial wall. To address this need, the delivery assembly 610 and / or the attenuation device 200 may optionally include a tensioning mechanism to tension or provide a tensile stress to the second anchor member 204b, thereby increasing the length of the attenuation member 202 and / or the distance between the first and second anchor members 204a and 204b. 8C, the second anchoring member 204b can include one or more connecting portions 205 (e.g., one or more eyelets extending proximally from the anchoring frame) and one or more connecting members 618 (e.g., sutures, threads, filaments, tethers, etc.) extending between the second anchoring member 204b and a proximal portion (not shown) (e.g., a handle) of the delivery assembly 610. The connecting members 618 are configured to releasably engage the connecting portions 205 to mechanically connect the second anchoring member 204b to the proximal portion of the delivery assembly 610. A clinician can apply tension to the connecting members 618 to elongate the attenuation device 200 and / or the attenuation member 202 and adjust the longitudinal position of the second anchoring member 204b. Once the second anchoring member 204b is positioned in a desired longitudinal position relative to the first anchoring member 204a and / or the local anatomy, the second anchoring member 204b can be expanded (e.g., by deployment of one or more expandable members) to contact the arterial wall. Before, during, and / or after expansion of the second anchoring member 204b, the linking member(s) 618 can be disengaged from the second anchoring member 204b. For example, in some embodiments, an operator can cause the linking members 618 to break along their length by applying a tension force that is less than the force that would be required to remove one or both of the first anchoring member 204a and the second anchoring member 204b. Once disengaged from the second anchoring member 204b and / or the attenuation device 200, the linking member(s) 618 can be withdrawn from the treatment site through the guide catheter 604.

[0109] In other embodiments, other tensioning mechanisms may be utilized. For example, in some embodiments, the attenuation device 200 includes a releasable clasp, ring, or hook that is selectively releasable by an operator. The clasp, ring, or hook may be of any type that allows the thread to be secured to the second anchoring member 204b and can be selectively opened or released to disengage the thread from the second anchoring member 204b. The release may be controlled by the clinician from an extracorporeal location. Although the tensioning mechanism is described herein with respect to the second anchoring member 204b, it should be understood that other portions of the attenuation device 200 and / or delivery assembly 610 (such as the first anchoring member 204a) may be coupled to the tensioning mechanism.

[0110] In certain embodiments, the damping member 202 and / or the individual anchoring members 204a, 204b may be self-expanding. For example, the delivery assembly 610 may include a delivery sheath (not shown) that surrounds and radially constrains the attenuation device 200 during delivery to the treatment site. Upon reaching the treatment site, the delivery sheath may be at least partially withdrawn or retracted to allow the damping member 202 and / or the individual anchoring members 204a, 204b to expand. In some embodiments, the expansion of the anchoring members 204 may drive the expansion of the damping member 202. For example, the anchoring members 204 may be fixedly attached to the damping member 202, and the expansion of one or both anchors 204 pulls or pushes the damping member 202 radially outward (depending on the relative positioning of the damping member 202 and the anchoring members 204).

[0111] As best shown in FIG. 8C, when the attenuation device 200 is positioned at a treatment site (e.g., in the left or right common carotid artery), oxygenated blood ejected from the left ventricle flows through the lumen 214 of the attenuation member 202. When the blood comes into contact with the attenuation region 220 of the attenuation member 200, the attenuation region 220 deforms and absorbs some of the blood's pulsatile energy, thereby reducing the magnitude of pulse pressure transmitted to portions of the artery distal to the attenuation device 202 (such as the more sensitive cerebral arteries). The attenuation region 202 acts as a pressure limiter that distributes the pressure during the systolic phase of the cardiac cycle more evenly downstream of the attenuation device 200 without unduly compromising blood flow through the attenuation device 200. Thus, the attenuation device 200 reduces pulsatile stress on downstream portions of the arterial network, preventing or at least partially mitigating the onset of vascular dementia and / or age-related dementia.

[0112] In some procedures, it may be beneficial to deliver multiple attenuation devices 200 to multiple arterial locations. For example, after deploying a first attenuation device 200 at a first arterial location (e.g., left or right common carotid artery, internal or external carotid artery, ascending aorta, etc.), the clinician may position and deploy a second attenuation device 200 at a second arterial location different from the first arterial location (e.g., left or right common carotid artery, internal or external carotid artery, ascending aorta, etc.). In certain applications, a first attenuation device is deployed at the left common carotid artery and a second attenuation device is deployed at the right common carotid artery. In other embodiments, two or more attenuation devices 200 may be delivered simultaneously.

[0113] In some embodiments, an additional stent of larger diameter may be placed within the vessel prior to deployment of the attenuation device 200 to expand the vessel diameter in preparation for the device. The attenuation device 200 may then be deployed within the larger stent. This deployment may help reduce the impact on the remaining diameter of the vessel, thereby reducing the impact on blood flow.

[0114] 9A-9F are schematic cross-sectional views of several embodiments of damping members according to the present technology. In FIGS. 2A-9F, like reference numbers refer to similar or identical components. In the embodiment shown in FIG. 9A, the inner surface 212 of the damping member 202 is curved along its entire length. The distance between the outer surface 210 and the inner surface 212 gradually increases in the distal direction and then decreases. Thus, the damping region 220 extends the entire length of the damping member 202. FIGS. 9B and 9C illustrate embodiments of the damping member 202 in which the inner surface 212 has a series of damping regions 220 defined by undulations in the inner surface 212. In these embodiments, the distance t increases in the distal direction, then decreases, then increases, then decreases, and so on. In FIG. 9B, the damping region 220 is generally straight, while in FIG. 9C, the damping region 220 is generally curved. 9D-9E illustrate embodiments of damping member 202 having a damping region 220 comprising an annular ring that projects radially inward into lumen 214. One or more portions of the annular ring may flex longitudinally in response to blood flow. As shown in FIG. 9F, in some embodiments, damping member 220 can comprise two or more opposing leaflets 221.

[0115] II. SELECTED ABLATION EMBODIMENTS OF THE ATTENUATION DEVICE 10 and 11 are schematic cross-sectional views of some embodiments of attenuation devices according to the present technology. In FIGS. 2A-15, like reference numbers refer to similar or identical components. For example, FIG. 10 shows an attenuation device 1000 comprising only an attenuation member 202. A portion of an arterial wall A can be resected, and the attenuation member 202 can be coupled (e.g., by a suture 1002) to the open end of the resected artery, such that the attenuation member 202 spans the resected portion of the artery A. In some embodiments, the attenuation member 202 may have a generally cylindrical shape with a constant wall thickness, as shown in FIG. 11. In such embodiments, the inner diameter ID of the attenuation member 202 may be generally constant along the length of the attenuation member 202. In operation, the attenuation devices 1000 and 1100 shown in FIGS. 10 and 11 are highly flexible elastic members that expand radially outward as a systolic pressure wave passes through the attenuation devices 1000 and 1100. Because the resected portions of the arterial wall A cannot limit the expansion of the attenuation devices 1000 and 1100, these devices are able to expand and absorb more energy from the blood flow than the native arterial wall A.

[0116] III. SELECTED ADDITIONAL EMBODIMENTS OF THE DAMPING DEVICE 12A-19B illustrate additional embodiments of attenuation devices constructed in accordance with the present technology. For example, FIG. 12A shows an attenuation device 1200 comprising an attenuation member 1202 coupled at a proximal end and a distal end to anchoring members 1204a and 1204b. The attenuation member 1202 comprises strands 1203 having a preset helical configuration such that in a deployed state, the strands 1203 form a generally tubular structure defining a lumen through which the strands 1203 extend. The tubular structure has an inner surface 1209 (FIG. 12B) and an outer surface 1211. The strands 1203 may be formed of any suitable biocompatible material, such as one or more elastic polymers configured to stretch in response to radially outward forces exerted on the helical strands by pulse waves. In some embodiments, the strands 1203 may additionally or alternatively comprise one or more metals, such as stainless steel, and / or a superelastic and / or shape memory alloy, such as Nitinol. In certain embodiments, the damping member 1202 may be made from a recombinant human protein such as tropoelastin or elastin.

[0117] The anchoring members 1204a and 1204b may be generally similar to the anchoring members 104a and 104b described with respect to Figures 2A-2C. In some embodiments, the attenuation device 1200 includes more or less than two anchoring members 1204 (one anchoring member, three anchoring members, etc.). In certain embodiments, the attenuation device 1200 does not include an anchoring member 1204.

[0118] In the deployed state, the damping member 1202 is configured to be wrapped around an artery that supplies blood to the brain. For example, in the embodiment shown in FIG. 12A, the damping member 1202 is configured to be positioned around the exterior of artery A such that an inner surface 1209 of the damping member 1202 contacts the outer surface of artery A (see FIG. 12B). In other embodiments (not shown), the damping member 1202 is configured to be positioned around the lumen of the artery such that an outer surface 1211 of the damping member 1202 contacts the inner surface of the arterial wall.

[0119] 12B is a cross-sectional side view of the attenuation device 1200 during the transmission of a pulse wave (PW) through a portion of the artery A surrounded by the attenuation device 1200. In FIG. 12B, the dashed line A represents the artery during diastole, or when the artery is relaxed. The solid line A′ represents the artery in response to a pulse wave PW traveling through the artery during systole. As shown in FIG. 12B, as a wave front (WF) (or leading edge of the pulse wave PW) travels through the artery, the wave front travels along an axial position L corresponding to the wave front WF. 1 The wave front WF pushes the arterial wall radially outward against the coil, thereby expanding the artery A. The wave front WF pushes the arterial wall radially outward against the coil, thereby expanding the artery A. 1 For example, in an embodiment in which the strands 1203 are made of a stretchable material such as an elastic polymer, the coils are expanded radially by the portion R 1 , and expand along the arterial wall to accommodate the pulse wave, thereby absorbing a portion of the energy transmitted by the pulse wave and reducing stress on the arterial wall. In any of the above embodiments, the portion of the coil distal or proximal to the area affected by the wave is contracted (R 2 ), thereby constricting the artery to its relaxed diameter. This constriction of the artery creates a temporary impedance to the pulse wave that absorbs some of the energy. Once the pulse wave has passed, the arterial wall returns to its relaxed state.

[0120] FIG. 13 illustrates another embodiment of an attenuation device 1300 according to the present technology. As shown in FIG. 13, the attenuation device 1300 can include a damping member 1302 defined by an extravascular wrap. The damping member 1302 may be made from a generally rectangular section of a suitable biocompatible elastically deformable material configured to be wrapped around a blood vessel. Alternatively, the damping member 1302 may be initially provided having a cylindrical shape including a longitudinal slit 1304 for receiving the blood vessel. The damping member 1302 may be made from a composite such as an elastic polymer, a shape memory and / or superelastic material such as Nitinol (nickel titanium), a recombinant human protein such as tropoelastin or elastin, as well as other suitable materials. As shown in FIG. 13, the damping member 1302 is configured to be secured around an artery (e.g., a carotid artery) between the aortic arch and the junction where the left common carotid artery divides into the internal carotid artery (IC) and the external carotid artery (EC). Alternatively or additionally, it will be understood by those skilled in the art that the damping member 1302 may be deployed around the brachiocephalic trunk (not shown) or right common carotid artery (not shown), or a distal branch of any of the aforementioned arteries, or a proximal branch of any of the aforementioned arteries, such as the ascending aorta. Opposing edges of the damping member 1302 may be secured together with a coupling device, such as sutures / sutures 1310, staples, or another coupling device, such that the outer diameter of the artery is reduced. In some embodiments, the coupling device may be made of an elastic material, such that it stretches to receive the pulse wave and absorb its energy. The elastically deformable damping member 1302 is adapted to radially expand during the systolic phase and radially contract during the diastolic phase. The damping member 1302 is secured such that the inner diameter of the elastically deformable material is smaller than the initial outer diameter of the artery during the systolic phase, but not smaller than the outer diameter of the artery during the diastolic phase.

[0121] Figure 14 depicts another embodiment of an attenuation device 1400 for treating an arterial vessel. The device 1400 may be structurally similar to the attenuation device 1300 shown in Figure 13, except that two opposing edges of the elastically deformable damping member 1402 of Figure 14 are secured together using a Ziplock® type coupling mechanism 1410.

[0122] FIG. 15 illustrates another embodiment of an attenuation device 1500 configured in accordance with the present technology. The attenuation device 1500 includes a generally tubular anchoring member 1504 (e.g., a stent, mesh, braid, etc.) defining a lumen 1514 therethrough. The anchoring member may be made of a resilient biocompatible material, such as stainless steel, titanium, nitinol, etc. In some embodiments, the anchoring member 1504 is made of a shape memory and / or superelastic material. The radially outer surface of the anchoring member 1504 is configured to be positioned in apposition with an inner surface of an arterial wall. The radially inner surface of the anchoring member 1504 is lined or otherwise coated with an absorbent material 1503 (e.g., a cushioning material), such as an elastically deformable material adapted to absorb shock. The lumen 1514 is configured to receive blood flow therethrough. The lumen 1514 is present when the anchoring member 1504 is radially expanded, but may not be present in an initial contracted configuration prior to deployment.

[0123] In some embodiments (not shown), the attenuation device can be a biocompatible gel that is injected around a portion of the left or right carotid artery or brachiocephalic artery. The gel increases the external pressure acting on the artery, thus decreasing the external diameter of the artery. When blood pressure increases in the artery, the gel elastically deforms, causing the artery to radially expand during the systolic phase and radially contract during the diastolic phase.

[0124] FIG. 16A is a perspective cutaway view of an attenuation device 1600 according to the present technology in a deployed, relaxed state. FIG. 16B is a cross-sectional view of the attenuation device 1600 positioned in an artery A during transmission of a pulse wave PW through a portion of the artery A surrounded by the attenuation device 1600. Referring together to FIG. 16A and FIG. 16B, the attenuation device 1600 includes an attenuation member 1602 and a structural member 1604 coupled to the attenuation member 1602. In FIG. 16A, an intermediate portion of the structural member 1604 has been removed to show the structural features of the attenuation member 1602. As shown in FIG. 16A, the attenuation device 1600 can have a generally cylindrical shape in the deployed, relaxed state. The attenuation device 1600 can be configured to wrap around the circumference of an artery with opposing longitudinal edges (not shown) secured to one another via sutures, staples, adhesives, and / or other suitable coupling devices. Alternatively, the attenuation device 1600 can have a longitudinal slit for receiving the artery therethrough. In any of the above-described extravascular embodiments, the attenuation device 1600 is configured to be positioned around the circumference of the artery A such that the inner surface 1612 (FIG. 16B) is adjacent to and / or in contact with the outer surface of the arterial wall. In other embodiments, the attenuation device 1600 can be configured to be positioned intravascularly (e.g., within the arterial lumen) such that the outer surface of the attenuation device 1600 is adjacent to and / or in contact with the inner surface of the arterial wall. In such intravascular embodiments, the inner surface 1612 of the attenuation member 1602 is adjacent to or in direct contact with blood flowing through the artery A.

[0125] The structural member 1604 can be a generally cylindrical structure configured to expand from a low-profile state to a deployed state. The structural member 1604 is configured to provide structural support for anchoring the attenuation device 1600 to a selected region of the artery. In some embodiments, the structural member 1604 can be a stent formed from a superelastic and / or shape memory material (e.g., Nitinol) or a laser cut metal such as stainless steel. All or a portion of the structural member 1604 can include a radiopaque coating to improve visualization of the device 1600 during delivery, and / or the structural member 1604 may include one or more radiopaque markers. In other embodiments, the structural member 1604 may comprise a mesh or woven (e.g., braided) structure in addition to or in lieu of a laser cut stent. For example, the structural member 1604 can include a tube or braided mesh formed from a plurality of flexible wires or filaments arranged in a diamond pattern or other configuration. In some embodiments, all or a portion of the structural member 1604 can be covered with a graft material (such as Dacron) to promote a seal with the vessel wall. Additionally, all or a portion of the structural member 1604 can include one or more biomaterials.

[0126] In the embodiment shown in FIGS. 16A and 16B, the structural member 1604 is positioned radially outward of the damping member 1602 and extends along the entire length of the damping member 1602 (although in FIG. 16A, an intermediate portion of the structural member 1604 is cut away for illustrative purposes only). In other embodiments, the structural member 1604 and the damping member 1602 may have other suitable configurations. For example, the damping device 1600 may include more than one structural member 1604 (e.g., two structural members, three structural members, etc.). Additionally, in some embodiments, the structural member(s) 1604 may extend along only a portion of the damping member 1602 such that a portion of the length of the damping member 1602 is not surrounded by and / or axially aligned with any portion of the structural member 1604. Also, in some embodiments, all or a portion of the damping member 1602 may be positioned radially outward of all or a portion of the structural member 1604.

[0127] 16A and 16B, the damping member 1602 includes a proximal damping element 1606a and a distal damping element 1606b. The damping member 1602 may further include an optional channel 1608 extending between the proximal and distal damping elements 1606a, 1606b. The channel 1608 may, for example, extend longitudinally along the attenuation device 1600 and fluidly couple the proximal damping element 1606a to the distal damping element 1606b. The damping member 1602 may further include a mitigating material 1610 configured to deform in response to fluid stress (such as blood flow) to thereby absorb at least a portion of the stress. For example, as best shown in FIG. 16B, in one embodiment, the mitigation material 1610 includes a plurality of fluid particles F (only one fluid particle is labeled) contained within the proximal damping element 1606a, the distal damping element 1606b, and the channel(s) 1608. As used herein, the term "fluid" refers to liquid and / or gas, and "fluid particles" refers to liquid particles and / or gas particles. In some embodiments, the damping member 1602 is a gel, and a plurality of fluid particles F are dispersed within a network of solid particles. In other embodiments, the damping member 1602 may include only fluid particles F (e.g., only gas particles, only liquid particles, or only gas and liquid particles) contained within a flexible and / or elastic membrane that defines the proximal damping member 1606a, the distal damping member 1606b, and the channel(s) 1608. The viscosity and / or composition of the mitigation material 1610 may be the same or vary along the length and / or circumference of the damping member 1602 .

[0128] In the embodiment shown in FIGS. 16A and 16B, the channel 1608 is spaced apart from the static radial thickness t r and circumferential thickness t c Static radial thickness t less than r and circumferential thickness t c(FIG. 16A). As best shown in FIG. 16A, in some embodiments, the proximal and distal damping elements 1606a, 1606b may extend around the entire circumference of the attenuation device 1600, and the channel 1608 may extend around only a portion of the circumference of the attenuation device 1600. In other embodiments, the channel 1608 is spaced apart from the rest radial thickness t of the proximal and distal damping elements 1606a, 1606b. r Approximately the same static radial thickness t r (see damping elements 1906a-1906c and channel 1908 in FIGS. 19A and 19B ), and / or the static circumferential thickness t c Approximately the same static circumferential thickness t c may have the following structure:

[0129] Referring to FIG. 16B, a pulse wave PW traveling through artery A reaches a first axial position L along the length of damping member 1602. 1 (e.g., on the wavefront WF), at least a portion of the fluid particles are moved along the length of the damping member 1602 to a first axial position L 1 A second axial position L away from 2 Thus, at least a portion of the fluid particles are redistributed along the length of the damping member 1602, causing the inner diameter ID of the damping member 1602 to move toward the first axial position L 1 and at another axial position (e.g., L 2) such that the inner diameter ID of the attenuation device 1600 decreases. For example, as the wavefront WF passes through the proximal portion 1600a of the device 1600, the portion of the artery A aligned with the wavefront WF expands, thereby stressing the proximal attenuation element 1606a and displacing at least a portion of the fluid particles within the proximal attenuation element 1606a distally within the attenuation member 1602. At least a portion of the displaced fluid particles are forced through the channel(s) 1608 into the distal attenuation element 1606b, thereby increasing the volume of the distal attenuation element 1606b and causing the inner diameter ID of the attenuation device 1600 to decrease at the distal portion 1600b. The decrease in the inner diameter ID of the attenuation device 1600 provides an impedance to the blood flow that absorbs at least a portion of the energy of the pulse wave as the blood flow reaches the distal attenuation member 1606b. Thereafter, as the wavefront WF passes through the distal portion 1600b of the device 1600, the portion of the artery A aligned with the wavefront WF expands, thereby stressing the distal attenuation element 1606b and displacing at least a portion of the fluid particles currently within the distal attenuation element 1606b proximally within the attenuation member 1602. At least a portion of the displaced fluid particles are forced through the channel(s) 1608 into the proximal attenuation element 1606a, thereby increasing the volume of the proximal attenuation element 1606a and decreasing the inner diameter ID of the device 1600 at the proximal portion 1600a. The displacement of the fluid particles and / or deformation of the attenuation member 1602 in response to the pulse wave absorbs at least a portion of the energy carried by the pulse wave, thereby reducing stress on the arterial wall distal to the device.

[0130] As the damping member 1602 deforms in response to a pulse wave, the shape of the structural member 1604 may remain generally unchanged, thereby assisting in facilitating redistribution of fluid particles within and along the damping member 1602. In other embodiments, the structural member 1604 may also deform in response to local fluid stresses.

[0131] 17A is a perspective view of another embodiment of an attenuation device 1700 according to the present technology. FIG. 17B is a cross-sectional view of the attenuation device 1700 positioned in an artery A during transmission of a pulse wave PW through a portion of the artery A surrounded by the attenuation device 1700. The attenuation device 1700 may include a structural member 1704 and a damping member 1702. The structural member 1704 may be generally similar to the structural member 1604 shown in FIG. 16A and FIG. 16B. The damping member 1702 is defined by a single chamber 1705 containing the mitigation substance 1610 and a plurality of baffles 1720 that separate the chamber 1705 into three fluidly connected compartments 1706a, 1706b, and 1706c. The baffles 1720 extend only a portion of the radial thickness of the damping member 1702, thereby leaving a gap G between the end of the baffle 1720 and an inner wall 1722 of the damping member 1702. In other embodiments, the attenuation device 1700 may include more or fewer sections (e.g., a single tubular section (no baffle), two sections, four sections, etc.). Additionally, the baffle 1720 may extend around all or a portion of the circumference of the damping member 1702.

[0132] FIG. 18A is a perspective view of another embodiment of an attenuation device 1800 according to the present technology, and FIG. 18B is a front view of the attenuation device 1800 positioned around an artery A, shown in a deployed state. Referring together to FIGS. 18A-18B, the attenuation device 1800 includes a generally tubular sidewall 1805 defining a lumen in a deployed, relaxed state. The attenuation device 1800 can be formed from generally parallelogram elements that are wrapped in a helical configuration around a mandrel and heat set. In other embodiments, the attenuation device 1800 can have other suitable shapes and configurations in the unfolded, undeployed state. As shown in FIG. 18B, in the deployed state, the attenuation device 1800 is configured to be helically wrapped around or around the circumference of an artery that supplies blood to the brain. Opposing longitudinal edges 1807 of the attenuation device 1800 come together in the deployed state to form a helical path along the longitudinal axis of the artery A. The attenuation device 1800 may include any of the connecting devices described with respect to Figures 13-15 for securing all or a portion of the opposing longitudinal edges to one another.

[0133] As best shown in FIG. 18A, the sidewall 1805 of the attenuation device 1800 includes a structural member 1804 and a damping member 1802. The structural member 1804 may be generally similar to the structural member 1604 shown in FIG. 16A and FIG. 16B, except that the structural member 1804 in FIG. 18A and FIG. 18B has a helical configuration in the deployed state. The damping member 1802 may be generally similar to any of the damping members described herein, particularly those described with respect to FIG. 13-17B and FIG. 19A and FIG. 19B. In the embodiment shown in FIG. 18A and FIG. 18B, the damping member 1802 is positioned radially inward of the structural member 1804 when the attenuation device 1800 is in the deployed state. In other embodiments, the damping member 1802 may be positioned radially outward of the structural member 1804 when the attenuation device 1800 is in the deployed state.

[0134] The attenuation device 1800 may be configured to wrap around the circumference of the artery A such that the inner surface 1812 ( FIG. 18A ) is adjacent to and / or in contact with the outer surface of the arterial wall. In other embodiments, the attenuation device 1800 may be configured to be positioned intravascularly (e.g., within the arterial lumen) such that the outer surface of the attenuation device 1800 is adjacent to and / or in contact with the inner surface of the arterial wall. In such intravascular embodiments, the inner surface 1812 of the attenuation member 1802 is adjacent to or in direct contact with blood flowing through the artery A.

[0135] 19A and 19B are perspective and top views, respectively, of an attenuation device 1900 that may define one embodiment of the attenuation device 1800 shown in FIGS. 18A and 18B. In FIGS. 19A and 19B, the attenuation device 1900 is shown in an unfolded, undeployed state. The attenuation device 1900 includes an attenuation member 1902 having a plurality of chambers 1906a, 1906b, 1906c spaced apart along a longitudinal dimension of the attenuation device 1900 in the unfolded state. The chambers 1906a, 1906b, 1906c may be fluidly connected by channels 1908 extending between adjacent chambers. Thus, the attenuation device 1900 may operate in a manner similar to the attenuation device 1600, where a mitigation substance (not shown in FIGS. 19A and 19B) in the chambers 1906a-1906c travels through the channels 1908 to expand / contract the individual chambers in response to pressure waves traveling through a blood vessel. Movement of the mitigating material within chambers 1906 a - c attenuates the energy of the pulse wave and reduces the impact of the pulse wave distal to the attenuation device 1900 .

[0136] IV. Selected Therapeutic Agents for Treating Neurological Conditions In addition to providing an implantable attenuation device, the present technology includes providing a therapeutic agent for treating a neurological disorder. Those skilled in the art will understand that the therapeutic agents discussed herein are illustrative of the types of therapeutic agents in the present technology, and that the present technology is not limited to the therapeutic agents explicitly discussed herein. For example, therapeutic agents that are not explicitly described herein but are within the classes of therapeutic agents provided herein and / or that treat the neurological conditions discussed herein are included in the present technology.

[0137] Therapeutic agents for treating neurological conditions, such as neurocognitive and / or neurodegenerative disorders, include therapeutic agents approved for use in human subjects by the United States Food and Drug Administration ("FDA"), therapeutic agents currently undergoing clinical trials to investigate use in human subjects, such as clinical trials compliant with the FDA or other similar organizations in other countries, preclinical therapeutic agents, and any other therapeutic agents for or intended to treat a neurological condition, e.g., investigational therapeutic agents, therapeutic agents in development or otherwise under consideration for development, and therapeutic agents identified as potentially useful for treating or intended to treat a neurological condition. Examples of neurological conditions, such as neurocognitive disorders, neurodegenerative disorders, or other neurological disorders, include, but are not limited to, Alzheimer's disease, mild Alzheimer's disease, prodromal Alzheimer's disease, mild cognitive impairment, cerebral amyloid angiopathy, frontotemporal dementia, vascular dementia, age-related dementia, amyloidosis, Lewy body disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich's ataxia, and traumatic brain injury. In some embodiments, these therapeutic agents represent more than one class of therapeutic agents, more than one mechanism of action, more than one therapeutic target, and more than one therapeutic purpose.

[0138] The therapeutic agents discussed herein have different therapeutic purposes, such as disease-modifying therapeutic agents, symptomatic nootropics, and / or symptomatic agents that address neuropsychiatric and behavioral changes. Disease-modifying therapeutic agents, for example, alter the pathophysiology of a neurological condition. Symptomatic therapeutic agents, for example, reduce and / or alleviate symptoms associated with a neurological condition. In some embodiments, the therapeutic agent is both a disease-modifying therapy and a symptomatic therapy. In some embodiments, the therapeutic agent may include more than one therapeutic agent.

[0139] In some embodiments, the therapeutic agents of the present technology are members of the general classes of therapeutic agents including, but not limited to, EDG receptor family modulators, MMP inhibitors, and senolytic agents.

[0140] In some embodiments, the therapeutic agents of the present technology have different mechanisms of action. In some embodiments, the therapeutic agents are selected for administration to a subject in need thereof based on their mechanisms of action. For example, some therapeutic agents for treating neurological conditions, such as Alzheimer's disease, prevent abnormal cleavage of amyloid precursor protein in the subject's brain. In some embodiments, the therapeutic agent prevents expression and / or accumulation of β-amyloid protein (Aβ) in the subject's brain. For example, some therapeutic agents for treating neurological conditions, such as Alzheimer's disease, reduce systemic inflammation, blood-brain barrier inflammation, systemic inflammation, blood-brain barrier inflammation, or neuroinflammation in a subject. In some embodiments, the therapeutic agent for treating neurological conditions, such as Alzheimer's disease, has an endothelial protective effect. In some embodiments, the therapeutic agent treats, prevents, or delays Alzheimer's disease, other neurological conditions, or cognitive decline by reducing inflammation (e.g., blood-brain barrier inflammation, neuroinflammation, systemic inflammation), by reducing reactive oxygen species (e.g., oxidative stress), by reducing ischemia, and / or by reducing amyloid beta. For example, inflammation can be reduced by directly or indirectly reducing the levels of one or more cytokines, chemokines, and / or inflammatory markers in the subject (e.g., circulating or in the cerebrospinal fluid (CSF) of the subject), including VCAM-1, ICAM-1, TNFα, TGF-β, IL-6, IL-8, IL-1β, IL-12, and NF-κB, and / or by administering to the subject a peptide-based therapeutic, such as an IL-1Rα derivative (e.g., Anakinra®). Reactive oxygen species in the subject can be increased compared to before the subject has the condition, or compared to a subject without the condition. In other embodiments, the Therapeutic Agent treats, prevents, or delays Alzheimer's disease, other neurological conditions, or cognitive decline by inhibiting MMPs, by eliminating senescent cells, by improving tight junctions, or by inducing transcriptional activation of TIMPs.

[0141] Any of the therapeutic agents described herein, as well as other therapeutic agents that are members of the general class of therapeutic agents described herein, are administered in a therapeutically effective dose to a subject in need thereof before, during, or after positioning an implantable attenuation device within the subject (e.g., but not limited to, a subject with elevated forward compression wave intensity (FCWI) or a subject with elevated pulse pressure). Non-limiting pulse pressure elevation values ​​include a highest quartile carotid FCWI (mmHg m / s) of at least about 10,000. 3 ), a systolic blood pressure (mmHg) of at least about 125 mmHg, a pulse pressure of at least about 50 mmHg, a diastolic blood pressure of up to about 70 mmHg, and / or a mean arterial pressure of at least about 88 mmHg. In some embodiments, a carotid FCWI range (mmHg m / s 3 ), a systolic blood pressure (mmHg) of at least about 135 mmHg, a pulse pressure of at least about 55 mmHg, a diastolic blood pressure of up to about 75 mmHg, and / or a mean arterial pressure of at least about 95 mmHg. Without intending to be bound by any particular dose or dosing regimen, a therapeutically effective dose is an amount of a therapeutic agent that, when administered to a subject in need of the therapeutic agent, treats or at least partially treats, alleviates the effects of, or at least partially alleviates the effects of a condition in the subject (e.g., neurodegenerative condition, cognitive decline). Each therapeutically effective dose of a therapeutic agent is selected based on a variety of factors, including, but not limited to, one or more characteristics of the therapeutic agent (e.g., biological activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (e.g., age, sex, type and stage of disease, general health, responsiveness to a given dosage, and type of drug), and the route of administration.

[0142] A. EDG Receptor Family Modulators Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are lysophospholipids (LPL) that may have similar effects on cellular responses by acting on a common family of receptors. Endothelial Cell Differentiation Gene (EDG) receptors are a family of G-Protein Coupled Receptors (GPCRs) that function as receptors for both S1P and LPA. The EDG receptors, identified in Table 1 below, are divided into two subfamilies and named according to the ligand (S1P or LPA) they bind.

[0143] [Table 1]

[0144] Activation of EDG receptor by S1P or LPA has multiple effects on cells, including proliferation, cell survival, migration, differentiation, and cytoskeleton organization, and cytokine secretion. In addition to these effects, these S1P and LPA are involved in many pathophysiological processes, including inflammatory vascular disease, autoimmune disease, fibrotic disease, cancer, inflammation, and bone disease. Therefore, EDG receptor family modulators (e.g., S1P receptor agonists, LPA receptor agonists) can be used according to the embodiments described herein.

[0145] S1P has been shown to enhance endothelial barrier function, stimulate endothelial NO release through Akt-mediated phosphorylation of eNOS, and reconstitute high density lipoprotein. S1P also has anti-inflammatory properties and exerts protective effects against endotoxin-induced lung injury. In addition, S1P exhibits a strong effect on differentiation of adipose-derived stem cells into endothelial-like cells and upregulation of eNOS in these cells. These properties of S1P may contribute to its endothelial protective effect. Thus, in some embodiments, the EDG receptor family modulator is an S1P receptor agonist.

[0146] In some embodiments, the S1P receptor agonist is fingolimod (also known as FTY720 or Gilenya®), siponimod (Mayzent®), ozanimod, or ponesimod. These S1P receptor agonists may benefit blood-brain barrier integrity by activating S1P1 and / or S1P5. In certain embodiments, the S1P receptor agonist is fingolimod (also known as FTY720 or Gilenya®). FTY720 is an orally active S1P mimetic after phosphorylation to FTY720-P. Fingolimod was developed for therapy in the field of autoimmune diseases and organ transplantation, and is a clinically approved immunomodulatory therapy for multiple sclerosis. Fingolimod exhibits potent anti-inflammatory effects, and S1P receptor activation may result in the suppression of the progression of inflammatory vascular diseases, such as atherosclerotic lesions. Fingolimod has also been shown to promote angiogenesis, reduce ischemic brain damage, repair brain damage, and may have the ability to reverse blood-brain barrier damage (or preserve BBB integrity).Fingolimod has also been shown to attenuate infection-induced enhancement of Aβ accumulation.In another embodiment, the S1P receptor agonist is siponimod.Similar to fingolimod, siponimod has been shown to enhance BBB properties by regulating S1P1 and S1P5.

[0147] The EDG receptor family modulator can be administered at any therapeutically effective dose effective to treat a subject in need thereof. In certain embodiments, the effective dose corresponds to an FDA approved dose or any off-label use within the standard of care known to those skilled in the art. For example, in certain embodiments where fingolimod and / or siponimod are used, fingolimod and / or siponimod may be administered as recommended at a dose of 0.25mg, 0.5mg, 0.75mg, 1.0mg, 1.25mg, or 2mg. In other embodiments where ponesimod is used, ponesimod may be administered as recommended at a dose of 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, or 20mg. In other embodiments where ozanimod is used, ozanimod may be administered as recommended at a dose of 0.23mg, 0.46mg, or 0.92mg.

[0148] In other embodiments, the effective dose corresponds to a dose lower or higher than the FDA approved dose, for example, in some embodiments, the dose of the EDG receptor family modulator ranges from about 1 to about 500 μg / kg body weight. For example, the dosage is about 1 μg / kg to about 10 μg / kg, about 0.1 μg / kg to about 50 μg / kg, about 1 μg / kg to about 100 μg / kg, about 1 μg / kg to about 150 μg / kg, or about 1 μg / kg to about 200 mg / kg, about 1 μg / kg to about 250 μg / kg, about 1 μg / kg to about 300 μg / kg, about 1 μg / kg to about 350 μg / kg, about 1 μg / kg to about 400 μg / kg, about 1 μg / kg to about 450 μg / kg, about 1 μg / kg to about 500 μg / kg, about 1 μg / kg to about 750 μg / kg, or about 1 μg / kg to about 1 mg / kg, or about 1 μg / kg to about 2 mg / kg. For example, dosages include one or more doses of about 1 μg / kg, about 2.5 μg / kg, about 5 μg / kg, about 10 μg / kg, about 20 μg / kg, about 30 μg / kg, about 40 μg / kg, about 50 μg / kg, about 100 μg / kg, about 150 μg / kg, about 200 μg / kg, about 250 μg / kg, about 300 μg / kg, about 350 μg / kg, about 400 μg / kg, about 450 μg / kg, about 500 μg / kg, about 750 μg / kg, about 1 mg / kg, or about 2 mg / kg (or any combination thereof). In some embodiments, the EDG receptor family modulator is administered in an amount of less than about 0.001 mg, about 0.001 mg, about 0.01 mg, about 0.1 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0. 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, or a fixed dose of greater than about 20 mg.

[0149] In some embodiments, the EDG receptor family modulator is administered once a day, twice a day, or more than twice a day. In other embodiments, the EDG receptor family modulator is administered less frequently, for example, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week. In certain embodiments, the EDG receptor family modulator may be titrated, where the EDG receptor family modulator is administered at a low dose initially, and then incrementally increased until a desired effective dose is reached. In some embodiments, the EDG receptor family modulator is administered chronically. In some embodiments, the dosage of the EDG receptor family modulator is administered in one or more separate doses or by continuous infusion.

[0150] B. Matrix Metalloproteinase Inhibitors Matrix metalloproteinases (MMPs) encompass 23 secreted or cell surface proteases that act together and with other protease classes to shuffle extracellular matrix, cleave cell surface proteins, and alter the function of many secreted bioactive molecules. In the vasculature, MMPs affect the migration, proliferation, and apoptosis of vascular smooth muscle, endothelial cells, and inflammatory cells, thereby affecting intimal formation, atherosclerosis, and aneurysms. Thus, MMP inhibitors have been investigated for use in the treatment of vascular disease. For example, naturally occurring tissue inhibitors of MMPs (TIMPs), pleiotropic mediators such as tetracycline, chemically synthesized low molecular weight MMP inhibitors (MMPs), and inhibitory antibodies have all been shown to have effects in animal models of vascular disease. Thus, MMP inhibitors may be used in accordance with the embodiments described herein. In some embodiments, the MMP inhibitor is ilomastat, marimastat, prinomastat, batimastat, cipemastat, andecaliximab, or doxycycline. In certain embodiments, the MMP inhibitor is doxycycline.

[0151] In addition to such drugs that directly inhibit MMPs, other drugs may act to indirectly inhibit MMP-mediated processes. For example, glucocorticoids have been studied as therapeutic interventions to protect tight junctions and avoid BBB destruction in some cell and animal models. Glucocorticoids, such as dexamethasone, hydrocortisone, and corticosterone, induce improved tight junctions by increasing the level of tight junction proteins in vascular endothelial cells. This improvement in tight junctions by glucocorticoids is also associated with cytoskeleton reorganization. Moreover, dexamethasone in particular has been shown to inhibit cytokine-induced upregulation of MMP-9. Dexamethasone also induces transcriptional activation of TIMP-1 (tissue inhibitor of metalloproteinase-1) and TIMP-3, which may prevent MMP-9-mediated degradation of tight junction proteins. In addition, dexamethasone suppresses JMJD3 gene activation via putative negative glucocorticoid response element, and maintains the integrity of tight junctions in brain microvascular endothelial cells.Furthermore, administration of dexamethasone after BBB disruption has been found to promote the restoration of BBB integrity and prevent the subsequent increase in the production of inflammatory markers.Therefore, glucocorticoids such as dexamethasone can be used according to the embodiments described herein to act as both anti-inflammatory agents and indirect MMP inhibitors.

[0152] The MMP inhibitor can be administered at any therapeutically effective dose effective to treat a subject in need thereof, whether directly or indirectly. In certain embodiments, the effective dose corresponds to an FDA approved dose or any off-label use within the standard of care known to those of skill in the art. For example, in some embodiments, when doxycycline is used, doxycycline may be administered as recommended at a dose of 20 mg, 25 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 240 mg, or 300 mg; a daily dosage of 100 mg / day, 100-200 mg / day, or 200 mg / day. In other embodiments in which dexamethasone is used, it may be administered as recommended at doses of 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 6 mg, 7 mg, 8 mg, 10 mg, 20 mg; doses within the ranges of 4-8 mg, 8-12 mg, 4-24 mg, 10-100 mg; daily dosages of 0.2-6 mg / day, 0.75-9 mg / day, 3 mg / day, 30 mg / day; or at doses of 1-6 mg / kg body weight or 3 mg / kg body weight.

[0153] In other embodiments, the effective dose corresponds to a dose lower or higher than the FDA approved dose. For example, in some embodiments, the dose of the MMP inhibitor is in the range of about 0.1 to about 10 mg / kg body weight. For example, the dosage is about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 2 mg / kg, about 0.1 mg / kg to about 3 mg / kg, about 0.1 mg / kg to about 4 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 6 mg / kg, about 0.1 mg / kg to about 7 mg / kg, about 0.1 mg / kg to about 8 mg / kg, about 0.1 mg / kg to about 9 mg / kg, or about 0.1 mg / kg to about 10 mg / kg. For example, dosages include one or more doses of about 0.1 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.75 mg / kg, about 1.0 mg / kg, about 1.5 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10 mg / kg, or greater than about 10 mg / kg (or any combination thereof).In some embodiments, the MMP inhibitor is about 0.1 mg, about 1.5 mg, about 0.2 mg, about 2.5 mg, about 0.3 mg, about 3.5 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 20 mg, about The compound may be administered in a fixed dose of 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 400 mg, about 500 mg, about 1000 mg, or more.

[0154] In some embodiments, the MMP inhibitor is administered once a day, twice a day, or more than twice a day. In other embodiments, the EDG receptor family modulator is administered less frequently, for example, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week. In certain embodiments, the EDG receptor family modulator may be titrated, where the EDG receptor family modulator is administered at a low dose initially, and then incrementally increased until a desired effective dose is reached. In some embodiments, the MMP inhibitor is administered chronically. In some embodiments, the dosage of the MMP inhibitor is administered in one or more separate doses or by continuous infusion.

[0155] C. Senescent cell remover Senolytic agents are molecules that selectively eliminate senescent cells and are typically investigated as candidates for treating age-related diseases. Non-limiting examples of senolytic agents that can be used in accordance with the embodiments described herein include, but are not limited to, FOXO4-related peptides, bcl-2 inhibitors, Src tyrosine kinase inhibitors, USP7 (ubiquitin-specific processing protease 7) inhibitors, dasatinib, quercetin, fisetin, navitoclax, piperlongumine, azithromycin, roxithromycin, SSK1 (senescence-specific killing compound 1), Crispr / Cas9 used to knock out BIRC5 or other gene sequences (e.g., cancer or injury marker gene sequences), and kidney-type glutaminase 1 (GLS1) inhibitors.

[0156] In some embodiments, a combination of senolytic agents can be used in accordance with the methods and treatments discussed herein. In some embodiments, the combination of senolytic agents is a combination of dasatinib and quercetin (D+Q). D+Q has been found to reduce age-related brain inflammation, Aβ-associated oligodendrocyte progenitor senescence, and cognitive impairment in Alzheimer's disease models.

[0157] The senolytic agents (alone or in combination) can be administered at any therapeutically effective dose effective to treat a subject in need thereof. In certain embodiments, the effective dose corresponds to an FDA approved dose or any off-label use within the standard of care known to one of skill in the art. For example, in some embodiments in which dasatinib is used, dasatinib may be administered as recommended at a dose of 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg, 180 mg. In other embodiments in which quercetin is used, quercetin may be administered as recommended at a dose of 400 mg, 500 mg, 1000 mg, or 400-1400 mg. In certain embodiments in which the combination D+Q is used, D+Q may be administered at a dose of 100 mg dasatinib combined with 1000 mg quercetin, or any combination of the recommended doses listed above.

[0158] In other embodiments, the dosage of the senolytic agent (alone or in combination) ranges from about 0.0001 to about 500 mg / kg body weight, e.g., dosages are from about 0.1 mg / kg to about 500 mg / kg, from about 0.1 mg / kg to about 250 mg / kg, from about 0.1 mg / kg to about 100 mg / kg, from about 0.1 mg / kg to about 50 mg / kg, or from about 0.1 mg / kg to about 25 mg / kg. For example, dosages include one or more doses of about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 1.0 mg / kg, about 1.5 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, or about 500 mg / kg (or any combination thereof). In some embodiments, the senolytic agents (alone or in combination) are administered in a fixed dose of about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 500 mg, about 1000 mg, or more. For example, the senolytic agents (alone or in combination) are administered in 1 to 50 doses (e.g., the therapy may be delivered in a single dose, two doses, three doses, four doses, five doses, etc.). In some embodiments, the total dose administered is in the range of about 25 mg to about 5000 mg or more, about 50 mg to about 2500 mg, about 50 mg to about 2000 mg, about 50 mg to about 1500 mg, about 50 mg to about 1000 mg, about 50 mg to about 500 mg, about 50 mg to about 100 mg, or any other range that has a therapeutic effect on the condition of the subject.For example, the total dose administered can be about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 4000 mg, about 5000 mg, or more. In some embodiments, the senolytic agent (alone or in combination) is administered chronically. In some embodiments, the dosage of the senolytic agent (alone or in combination) is administered in one or more separate administrations or by continuous infusion.

[0159] Those skilled in the art will appreciate that the foregoing therapies and accompanying description are for illustrative purposes and do not limit the therapies that may be provided in a particular embodiment of the present technology. Thus, any therapy useful or designed to treat a neurological condition, such as a neurodegenerative condition, may be present in a particular embodiment of the present technology.

[0160] V. SELECTED METHODS OF TREATING NEUROLOGICAL CONDITIONS USING A COMBINATION OF IMPLANTABLE ATTENUATION DEVICES AND THERAPEUTIC AGENTS Reducing the pulse pressure of a subject using an implanted attenuation device has subsequent downstream effects on other factors that contribute to the onset, duration, and / or progression of the subject's condition (e.g., neurological condition). Combining the use of the device of the present disclosure to reduce the pulse pressure of a subject with a therapeutic agent that, when administered to a subject, enhances the effect of reducing the pulse pressure on certain outcomes, further reduces and prevents the onset, duration, and / or progression of the subject's neurological condition. Reducing these outcomes can result in reduced inflammation (e.g., neuroinflammation, systemic inflammation, blood-brain barrier inflammation), reduced reactive oxygen species (e.g., oxidative stress), reduced ischemia, restored blood-brain barrier integrity, and other benefits. This occurs in subjects suffering from conditions such as progressive cognitive impairment and dementia. Without intending to be limiting, it is believed that subjects with FCWI values ​​in the highest quartile will benefit from the reduction in FCWI, systolic acceleration time, systolic pressure, and / or pulse pressure values ​​achieved using the implanted attenuation device of the present disclosure.

[0161] Several biological pathways, such as those described herein, may contribute to a neurological condition (e.g., dementia). Without intending to be bound by any particular theory, it is believed that interfering with (e.g., altering, affecting, impairing, inhibiting, reducing, or otherwise altering) two or more biological pathways may be more effective in treating, preventing, or otherwise alleviating a subject's neurological condition and / or its symptoms than interfering with a single biological pathway. In this manner, the effect of combining the implantable attenuation device of the present technology with at least one therapeutic agent may be complementary, additive, or even synergistic compared to the effect of the implantable attenuation device alone and the therapeutic agent alone. Thus, by combining the implantable attenuation device with one or more therapeutic agents that affect these other factors, one or more effects of the condition are further treated and / or delayed.

[0162] As discussed above, the combination therapy of the present technology includes an implantable attenuation device and a therapeutic agent for treating and / or preventing progression of a condition. Some embodiments of the present technology are directed to combination therapy including, for example, an implantable attenuation device as described above in headings I-III and one or more therapeutic agents targeting these factors. Some of these therapeutic agents are described above in heading IV, including, but not limited to, EDG receptor family modulators, MMP inhibitors, and senolytic agents. When combined, the implantable attenuation device and therapeutic agent of the present technology have a greater effect on treating and / or preventing one or more aspects of a subject's condition compared to the effect of either the implantable attenuation device alone or the therapeutic agent alone. For example, an implantable attenuation device that reduces pulse pressure in a subject and a therapeutic agent that reduces systemic inflammation and promotes BBB integrity are provided, thereby treating and / or preventing progressive cognitive impairment and dementia. Subjects with elevated pulse pressure or who would otherwise benefit from pulse pressure reduction may also have a blood-brain barrier with increased permeability, one or more microbleeds, increased inflammation, increased oxidative stress, or other vascular dysfunction. The implantable attenuation device can be provided to a subject with elevated pulse pressure or who would otherwise benefit from a reduction in pulse pressure before, after, or simultaneously with therapeutic agents such as EDG receptor family modulators, MMP inhibitors, and senolytic agents.

[0163] The disclosed methods include methods for treating a patient having a condition, the method comprising: (a) determining whether the patient has elevated pulse pressure or elevated pulse wave intensity / FCWI and is able to detect blood-brain barrier dysregulation or permeability, reduced reactive oxygen species (e.g., oxidative stress), reduced microbleeds, reduced inflammation (e.g., systemic inflammation, blood-brain barrier inflammation, neuroinflammation), at least one circulatory or cerebrospinal fluid (CSF) abnormality, or (b) determining whether the patient has elevated pulse pressure or elevated pulse wave intensity / FCWI, and and / or has been previously diagnosed with microhemorrhage, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated circulating or CSF cytokine level, or a combination thereof; and / or (ii) monitoring the subject for or having been monitored for symptoms of elevated pulse pressure or elevated pulse wave intensity / FCWI, and blood-brain barrier dysregulation or permeability, oxidative stress, microhemorrhage, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated circulating or CSF cytokine level, or a combination thereof.In some embodiments, the method also includes (b) if the patient has previously had symptoms of blood-brain barrier dysregulation or permeability, oxidative stress, microhemorrhage, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, or a combination thereof, if the patient has previously been diagnosed with microhemorrhage, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, or a combination thereof, and / or has been monitored for symptoms of blood-brain barrier dysregulation or permeability, oxidative stress, microhemorrhage, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, or a combination thereof, (i) providing to the patient an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, and (ii) providing a device for treating and / or preventing one or more effects of the condition. In some embodiments, the method further comprises (c) providing the device for treating and / or preventing one or more effects of the condition if the patient has not previously been diagnosed with blood-brain barrier dysregulation or permeability, oxidative stress, microhemorrhage, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, or a combination thereof, if the patient has never had symptoms of blood-brain barrier dysregulation or permeability, oxidative stress, microhemorrhage, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or CSF cytokine, or a combination thereof.

[0164] FIG. 20 is a flow diagram illustrating a method 2000 for treating and / or preventing one or more effects of a condition in a subject. At block 2200, the method 2000 provides a device for treating and / or preventing one or more effects of a condition. The device is an implantable attenuation device of the present technology and is configured to be placed in juxtaposition with a blood vessel of a subject. As with other devices of the present technology, the device provided in method 2000 includes a flexible attenuation member having both an inner surface formed from a sidewall having one or more at least partially deformable portions and an outer surface. In addition, a mitigating substance is disposed within the partially deformable portion and configured to move longitudinally and / or radially therein in response to pulsatile blood flow in the blood vessel. At block 2600, the method 2000 provides an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent in combination with the implantable attenuation device to treat or delay one or more effects of the condition. In some embodiments, the EDG receptor family modulator, MMP inhibitor, or senolytic agent is provided to the subject prior to the implantation of the attenuation device, up to about 24 hours, up to about 7 days, up to about 4 weeks, up to about 12 months, or up to about 5 years. In other embodiments, the implantation of the attenuation device is provided to the subject prior to the implantation of the EDG receptor family modulator, MMP inhibitor, or senolytic agent, up to about 24 hours, up to about 7 days, up to about 4 weeks, up to about 12 months, or up to about 5 years.For example, the EDG receptor family modulator, MMP inhibitor, and / or implantable attenuation device are provided to the subject about 0 to about 24 hours, about 1 to about 20 hours, about 3 to about 12 hours, about 5 to about 10 hours, about 1 day to about 7 days, about 2 days to about 6 days, about 3 days to about 5 days, about 1 week to about 4 weeks, about 2 weeks to about 4 weeks, about 1 week to about 3 weeks, about 2 weeks to about 3 weeks, about 1 year to about 5 years, about 1 year to about 4 years, about 2 years to about 5 years, about 2 years to about 4 years, about 3 years to about 4 years, or about 4 years to about 5 years prior to the implantable attenuation device, EDG receptor family modulator, or MMP inhibitor, respectively.

[0165] The steps of the above methods and additional methods disclosed herein can be performed in any order. For example, step (b) can be performed after step (a) and before step (c). As another example, step (c) can be performed after step (a) and before step (b).

[0166] As described above under heading IV, the EDG receptor family modulator, MMP inhibitor, or senolytic agent of the methods of the present technology are provided to a subject by administration.

[0167] Devices useful for the methods of the present technology include implantable attenuation devices of the present disclosure, such as devices comprising a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions configured to move longitudinally and / or radially within the one or more at least partially deformable portions in response to pulsatile blood flow in a blood vessel, and a mitigation material disposed within one or more at least partially deformable portions of the sidewall configured to move longitudinally and / or radially within one of the partially deformable portions in response to pulsatile blood flow in the blood vessel.

[0168] When combined with an implantable attenuation device of the present technology, a therapeutic agent described herein is provided in a first dosage amount that is less than a second dosage amount of the same therapeutic agent provided in the absence of the implantable attenuation device (e.g., a subject receiving the therapeutic agent alone and not in combination with an implantable attenuation device). For example, a subject having a neurodegenerative condition, such as dementia, is provided with a smaller dose of Omni-Biotic before, during, or after the implantable attenuation device is provided, compared to a subject provided with a dose of Omni-Biotic without being provided with an implantable attenuation device.

[0169] In some embodiments, when combined with an implantable attenuation device of the present technology, a therapeutic agent described herein is provided at a first dosage regimen that is less than a second dosage regimen of the same therapeutic agent provided in the absence of an implantable attenuation device. For example, a subject having a neurodegenerative condition, such as dementia, is provided with a first dosage regimen of Omni-Biotic before, during, or after the implantable attenuation device is provided, compared to a subject provided with a second dosage regimen of Omni-Biotic without the implantable attenuation device being provided.

[0170] In some embodiments, when combined with an implantable attenuation device of the present technology, the therapeutic agent described herein is provided by a first route that is different from a second route that is provided in the absence of the implantable attenuation device. For example, a subject having a neurodegenerative condition, such as dementia, is provided with Omni-Biotic by a first route before, during, or after the implantable attenuation device is provided, compared to a subject that is provided with Omni-Biotic by a second route without being provided with an implantable attenuation device. In some embodiments, the route of administration includes delivering the therapeutic agent from the device to the subject, for example, by eluting a therapeutic agent previously stored in at least a portion of the device.

[0171] VI. SELECTED SYSTEMS FOR TREATING NEUROLOGICAL CONDITIONS USING A COMBINATION OF IMPLANTABLE ATTENUATION DEVICES AND THERAPEUTIC AGENTS In addition to the methods, attenuation devices, and therapeutic agents described herein, the present technology also includes associated systems for treating and / or preventing one or more effects of a condition of a subject. The systems of the present technology include an effective amount of at least one therapy for treating and / or preventing one or more effects of a condition, and a device for treating and / or preventing one or more effects of a condition. As described above, the devices of the present technology include at least a flexible attenuation member forming a generally tubular structure having an inner surface formed from a sidewall having one or more at least partially deformable portions, and a mitigating substance disposed within one partially deformable portion and configured to move longitudinally and / or radially therein in response to pulsatile blood flow in a blood vessel. In some embodiments, the therapy includes at least one or more therapeutic agents that can be delivered by the attenuation device. In these embodiments, the therapeutic agent is disposed within and / or delivered by at least one or more of the at least partially deformable portions of the attenuation device. An effective amount of the therapeutic agent can be released from the device upon at least partial deformation of one or more of the at least partially deformable portions of the attenuation device. EXAMPLES

[0172] VII. Examples The following examples are illustrative of various embodiments of the present technology. The embodiments described herein are directed to a treatment regimen including an attenuation device (e.g., any of the devices described in paragraphs

[93] to

[0136] above) and a therapy (e.g., any EDG receptor family modulator, including those discussed in any of paragraphs

[0140] to

[0145] above; any MMP inhibitor, including those discussed in any of paragraphs

[0146] to

[0148] above; and / or any senolytic agent, including those discussed in any of paragraphs

[0149] to

[0151] above). The treatment regimen is not limited to one therapy and may include one or more additional therapies. According to some embodiments, the treatment regimen can be used in a method of treating or preventing a neurological condition using a combination therapy comprising implanting or otherwise providing an attenuation device (e.g., any of the devices described in paragraphs

[93] to

[0136] above) and administering or otherwise providing a therapy (e.g., any EDG receptor family modulator, including those discussed in any of paragraphs

[0140] to

[0145] above; any MMP inhibitor, including those discussed in any of paragraphs

[0146] to

[0148] above; and / or any senolytic agent, including those discussed in any of paragraphs

[0149] to

[0151] above). In such embodiments, the attenuation device may be implanted or provided prior to, simultaneously with, or after the therapy. At any time during the combination therapy, one or more additional therapies may also be administered. Non-limiting examples of attenuation devices, treatments using the attenuation devices, combination treatments, and treatment regimens, as well as studies and models demonstrating the efficacy, benefits, and advantages of the treatments, are included in the Examples below.

[0173] A. Examples 1 to 16: Devices for treating and / or preventing the progression of dementia Example 1. A device for treating and / or preventing the progression of dementia, comprising: a flexible, compliant attenuation member configured to be positioned intravascularly within an artery at a treatment site, the attenuation member being deformable between a low-profile state and an expanded state for delivery to the treatment site, the attenuation member including a generally tubular sidewall having (a) an outer surface, (b) an inner surface defining a lumen configured to direct blood flow, (c) a first end, (d) a second end along a length of the attenuation member opposite the first end, and (e) an attenuation region between the first end and the second end, the inner surface and the outer surface being spaced apart a greater distance at the attenuation region than at either the first end or the second end; a first anchoring member coupled to the first end of the attenuation member and a second anchoring member coupled to the second end of the attenuation member, wherein in a deployed state, the first anchoring member and the second anchoring member extend radially to a deployed diameter configured to contact a portion of the arterial wall at the treatment site, thereby securing the attenuation member to the treatment site, and the first anchoring member and the second anchoring member extend along only a portion of the length of the attenuation member, such that at least a portion of the attenuation region is exposed between the first anchoring member and the second anchoring member and allows the attenuation member to expand to a diameter larger than the deployed diameter.

[0174] Example 2. The device of example 1, wherein the damping member is configured to deform in response to changes in blood / pulse pressure or pulse wave strength / FCWI elevation.

[0175] Example 3. A device as described in example 1 or example 2, wherein at a location along the damping member coinciding with the leading edge of a pulse pressure wave, the distance between the inner and outer surfaces of the damping member decreases in response to the pressure.

[0176] Example 4. A device according to any one of Examples 1 to 3, wherein the lumen of the damping member has an hourglass shape.

[0177] Example 5. The device of any one of Examples 1-4, wherein the exterior surface is generally cylindrical and the interior surface is contoured.

[0178] Example 6. The device of any one of Examples 1-5, wherein the first anchoring member and the second anchoring member are each an expandable stent.

[0179] Example 7. The device of any one of Examples 1-5, wherein the first fixation member and the second fixation member are each an expandable mesh.

[0180] Example 8. The device of any one of Examples 1-5, wherein the first anchoring member and the second anchoring member are each at least one of an expandable stent and an expandable mesh.

[0181] Example 9. The device of any one of Examples 1-8, wherein the first fastening member and the second fastening member are each positioned around a circumference of the damping member.

[0182] Example 10. A device described in any one of Examples 1 to 8, wherein at least a portion of each of the first fastening member and the second fastening member is positioned within the damping member and extends through at least a portion of the thickness of the side wall.

[0183] Example 11. A device described in any one of Examples 1 to 10, wherein the damping region is a first damping region and the damping member includes a plurality of damping regions between the first end and the second end.

[0184] Example 12. A device described in any one of Examples 1 to 11, wherein at least one of the first fixation member and the second fixation member comprises a plurality of fixation devices extending radially outward from the outer surface of the attenuation device.

[0185] Example 13. The device of any one of Examples 1-12, wherein the device is configured to be positioned at a treatment site within the left common carotid artery.

[0186] Example 14. A device according to any one of Examples 1 to 13, wherein the device is configured to be positioned at a treatment site within the right common carotid artery.

[0187] Example 15. A device according to any one of Examples 1 to 14, wherein the device is configured to treat Alzheimer's disease.

[0188] Example 16. A device described in any one of Examples 1 to 15, wherein the device is configured to reduce the occurrence of microhemorrhage in one or more branches of an artery downstream of the treatment site.

[0189] B. Examples 17-31: Devices for Treating Dementia Example 17. A device for treating dementia, comprising: an attenuation member configured for intravascular positioning within an artery at a treatment site and having a lumen configured to direct blood flow to distal vasculature, the attenuation member being deformable between a low-profile state for delivery to the treatment site and an expanded state, the attenuation member including an attenuation region having a pressure limiter that protrudes laterally inward into the lumen to distribute pressure downstream of the attenuation member as a pulse pressure wave propagates along the attenuation member during systole; and an anchoring member connected to the damping member, the anchoring member configured, in a deployed state, to extend outward to a deployed diameter and contact a portion of the vessel wall at the treatment site, thereby securing the damping member to the treatment site, the anchoring member extending along only a portion of the length of the damping member such that the damping region of the damping member is allowed to extend radially outward beyond the deployed diameter of the anchoring member.

[0190] Example 18. A device as described in Example 17, wherein the damping member is configured to deform in response to changes in blood / pulse pressure or pulse wave strength / FCWI increase.

[0191] Example 19. A device as described in Example 17 or Example 18, wherein at a position along the damping member coinciding with the leading edge of the pulse pressure wave, the distance between the inner surface and the outer surface of the damping member decreases in response to the pressure.

[0192] Example 20. A device described in any one of Examples 17 to 19, wherein the lumen of the damping member has an hourglass shape.

[0193] Example 21. The device of any one of Examples 17 to 20, wherein the anchoring member is an expandable stent.

[0194] Example 22. A device described in any one of Examples 17 to 20, wherein the fixation member is an expandable mesh.

[0195] Example 23. A device described in any one of Examples 17 to 20, wherein the fixation member is at least one of an expandable stent and an expandable mesh.

[0196] Example 24. A device described in any one of Examples 17 to 23, wherein the fastening member is positioned around the circumference of the damping member.

[0197] Example 25. A device described in any one of Examples 17 to 23, wherein at least a portion of the fastening member is positioned within the damping member and extends through at least a portion of the thickness of the side wall.

[0198] Example 26. A device described in any one of Examples 17 to 25, wherein the damping region is a first damping region and the damping member includes a plurality of damping regions between the first end and the second end.

[0199] Example 27. A device described in any one of Examples 17 to 26, wherein the fixation member includes a plurality of fixation devices extending radially outward from the outer surface of the attenuation device.

[0200] Example 28. A device described in any one of Examples 17 to 27, wherein the device is configured to be positioned at a treatment site within the left common carotid artery.

[0201] Example 29. A device described in any one of Examples 17 to 28, wherein the device is configured to be positioned at a treatment site in the right common carotid artery.

[0202] Example 30. A device described in any one of Examples 17 to 29, wherein the device is configured to treat Alzheimer's disease.

[0203] Example 31. A device described in any one of Examples 17 to 29, wherein the device is configured to reduce the occurrence of microbleeding in a portion of a blood vessel downstream of the treatment site.

[0204] C. Example 32: Device for Treating Dementia Example 32. A device for treating dementia, comprising: a flexible, compliant attenuation member configured to be positioned intravascularly within an artery at a treatment site, the attenuation member being deformable between a low-profile state and an expanded state for delivery to the treatment site, the attenuation member including a generally tubular sidewall having (a) an outer surface, (b) an inner surface defining a lumen configured to direct blood flow, (c) a first end, (d) a second end along a length of the attenuation member opposite the first end, and (e) an attenuation region between the first end and the second end, the inner surface and the outer surface being spaced apart a greater distance at the attenuation region than at either the first end or the second end; a first anchoring member coupled to the first end of the attenuation member and a second anchoring member coupled to the second end of the attenuation member, the first anchoring member and the second anchoring member extending radially to a deployed diameter configured to contact a portion of the vessel wall at the treatment site in a deployed state, thereby anchoring the attenuation member at the treatment site; A device in which as blood flows through the damping member during systole, the damping member absorbs a portion of the blood's pulsating energy, thereby reducing the magnitude of pulse pressure transmitted to a portion of the blood vessel distal to the attenuation device.

[0205] D. Examples 33 to 39: Devices for Treating Blood Vessels Example 33. A device for treating a blood vessel, comprising: an anchoring system having a first portion and a second portion; a cushioning member positioned between the first and second portions of the fixation system such that a portion of the cushioning member is not constrained by the fixation system, the cushioning member configured to absorb pulsating energy transmitted by blood flowing through the blood vessel.

[0206] Example 34. A device as described in Example 33, wherein the cushioning member is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0207] Example 35. A device for treating a blood vessel, comprising: an intravascular cushioning device having a proximal anchor and a distal anchor, the proximal anchor and the distal anchor each configured to abut an inner wall of the aorta; an elastically deformable member extending between the proximal anchor and the distal anchor; The device, wherein the elastically deformable member is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0208] Example 36. A device as described in Example 35, wherein a portion of the elastically deformable membrane positioned longitudinally between the proximal anchor and the distal anchor defines an area of ​​reduced internal cross-sectional area compared to the proximal anchor and the distal anchor when the elastically deformable membrane is radially relaxed.

[0209] Example 37. A device described in Example 35 or Example 36, wherein the proximal anchor and the distal anchor are each radially expandable between a first diameter before deployment and a second diameter after deployment.

[0210] Example 38. A device described in any one of Examples 35 to 37, further comprising one or more threads fixed to the proximal anchor.

[0211] Example 39. The device of example 38, wherein each thread is secured to an eyelet.

[0212] E. Examples 40-43: Devices for treating the left common carotid artery, the right common carotid artery, the brachiocephalic trunk, the ascending aorta, the internal carotid artery, or the abdominal aorta Example 40. A device for treating an artery selected from the left common carotid artery, the right common carotid artery, the brachiocephalic trunk, the ascending aorta, the internal carotid artery, or the abdominal aorta, comprising: a wrap made from an elastically deformable material; and an engagement formation adapted to secure two opposing edges of the wrap around the artery; The device, wherein the elastically deformable material is configured to radially expand during a systolic phase and radially contract during a diastolic phase.

[0213] Example 41. A device as described in Example 40, wherein the engagement formation comprises a suture and / or a staple.

[0214] Example 42. The device of Example 41, wherein the engagement portion comprises a Ziploc®.

[0215] Example 43. A device for treating the left common carotid artery, the right common carotid artery, the brachiocephalic trunk, or the ascending aorta, comprising: a proximal anchor configured to be wrapped around the artery; a distal anchor configured to be wrapped around the artery and longitudinally spaced apart from the proximal anchor; a helical band adapted to be wrapped around the artery, the helical band having a first end securable to the proximal anchor and an opposing second end securable to the distal anchor, the helical band adapted to radially expand during a systolic phase and radially contract during a diastolic phase.

[0216] F. Examples 44-85: Devices for treating and / or preventing the effects of dementia Example 44. A device for treating and / or preventing the effects of dementia, comprising: A device comprising: a damping member having a low-profile state and a deployed state, wherein in the deployed state, the damping member comprises a deformable, generally tubular sidewall having an outer surface and a longitudinally contoured inner surface, the sidewall being configured to be positioned in juxtaposition with a blood vessel wall to absorb pulsatile energy transmitted by blood flowing through the vessel.

[0217] Example 45. A device as described in Example 44, wherein the attenuation member is configured to be positioned in juxtaposition with at least one of the left common carotid artery, the right common carotid artery, and the brachiocephalic artery.

[0218] Example 46. A device described in Example 44 or Example 45, wherein the attenuation member is configured to be positioned in juxtaposition with the ascending aorta.

[0219] Example 47. A device described in any one of Examples 44 to 46, wherein the attenuation member is configured to be positioned in juxtaposition with the inner surface of the vessel wall.

[0220] Example 48. A device described in any one of Examples 44 to 46, wherein the attenuation member is configured to be positioned in juxtaposition with the outer surface of the vascular wall.

[0221] Example 49. A device described in any one of Examples 44 to 48, wherein the side wall has an inner diameter, and when the damping member is in a deployed state, the inner diameter increases in the axial direction and then decreases.

[0222] Example 50. A device described in any one of Examples 44 to 49, wherein the cross-sectional area decreases and then increases in the longitudinal direction.

[0223] Example 51. The device of any one of Examples 44 to 50, wherein the outer surface has a generally cylindrical shape.

[0224] Example 52. A device described in any one of Examples 44 to 50, wherein the outer surface has an undulating shape.

[0225] Example 53. A device described in any one of Examples 44 to 52, further comprising an anchoring member connected to the damping member and axially aligned with only a portion of the damping member, the anchoring member configured to engage the vascular wall and secure the damping member to the vascular wall.

[0226] Example 54. The fastening member is a first fastening member, and the device further comprises a second fastening member coupled to the damping member, the second fastening member comprising: in axial alignment with only a portion of the damping member; and A device described in any one of Examples 44 to 53, wherein the damping member is spaced apart from the first fixing member along the longitudinal axis of the damping member.

[0227] Example 55. A device described in any one of Examples 44 to 54, wherein the attenuation member does not restrict the diameter of the blood vessel wall when the attenuation member is positioned adjacent to the blood vessel wall.

[0228] Example 56. A device for treating and / or preventing the effects of dementia, comprising: 1. A device comprising: an elastic member having a low-profile state for delivery to a treatment site in a blood vessel wall and a deployed state, wherein in the deployed state the elastic member is configured to abut an arterial wall and form a generally tubular structure having an inner diameter, an outer diameter, an outer surface, and a contoured inner surface, at least one of the outer diameter and the inner diameter increasing and decreasing, respectively, in response to increases and decreases in pulse pressure within the blood vessel.

[0229] Example 57. A device as described in Example 56, wherein the elastic member is configured to be positioned in juxtaposition with at least one of the left common carotid artery, the right common carotid artery, and the brachiocephalic artery.

[0230] Example 58. A device described in Example 56 or Example 57, wherein the elastic member is configured to be positioned in juxtaposition with the ascending aorta.

[0231] Example 59. A device described in any one of Examples 56 to 58, wherein the elastic member is configured to be positioned in juxtaposition with the inner surface of the blood vessel wall.

[0232] Example 60. A device described in any one of Examples 56 to 58, wherein the elastic member is configured to be positioned in juxtaposition with the outer surface of the vascular wall.

[0233] Example 61. A device described in any one of Examples 56 to 60, wherein the side wall has an inner diameter, and when the elastic member is in an expanded state, the inner diameter increases in the axial direction and then decreases.

[0234] Example 62. A device described in any one of Examples 56 to 61, wherein the cross-sectional area decreases and then increases in the longitudinal direction.

[0235] Example 63. A device described in any one of Examples 56 to 62, wherein the outer surface has a generally cylindrical shape.

[0236] Example 64. A device described in any one of Examples 56 to 62, wherein the outer surface has an undulating shape.

[0237] Example 65. A device described in any one of Examples 56 to 64, further comprising an anchoring member connected to the elastic member and axially aligned with only a portion of the elastic member, the anchoring member configured to engage the vascular wall and secure the elastic member to the vascular wall.

[0238] Example 66. The fastening member is a first fastening member, and the device further comprises a second fastening member coupled to the elastic member, the second fastening member comprising: in axial alignment with only a portion of the resilient member; and 66. The device of example 65, wherein the elastic member is spaced apart from the first fastening member along the longitudinal axis of the elastic member.

[0239] Example 67. A device described in any one of Examples 56 to 66, wherein the elastic member does not restrict the diameter of the blood vessel wall when the elastic member is positioned adjacent to the blood vessel wall.

[0240] Example 68. A device for treating and / or preventing the effects of dementia, comprising: A device comprising: a damping member containing a mitigation substance, the damping member having a low-profile configuration and a deployed configuration, and when the damping member is in the deployed configuration, the damping member forms a generally tubular structure configured to be positioned along a circumference of an artery, such that when a pulse wave traveling through the artery applies stress to a first axial location along the length of the tubular structure, at least a portion of the mitigation substance moves away from the first location to a second axial location along the length of the tubular structure.

[0241] Example 69. The device described in Example 68, further comprising a structural element coupled to the damping member.

[0242] Example 70. A device described in Example 68 or Example 69, wherein in the deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.

[0243] Example 71. A device described in any one of Examples 68 to 70, wherein in the deployed state, the device has a pre-set spiral configuration.

[0244] Example 72. A device described in any one of Examples 68 to 71, wherein the damping member comprises a liquid.

[0245] Example 73. A device described in any one of Examples 68 to 72, wherein the damping member comprises a gas.

[0246] Example 74. A device described in any one of Examples 68 to 73, wherein the damping member comprises a gel.

[0247] Example 75. A device described in any one of Examples 68 to 74, wherein the attenuation member is configured to be positioned in juxtaposition with the outer surface of the arterial wall in the deployed configuration.

[0248] Example 76. A device described in any one of Examples 68 to 74, wherein the attenuation member is configured to be positioned around the arterial wall in the deployed configuration, such that the inner surface of the attenuation member comes into contact with blood flowing through the artery.

[0249] Example 77. A device for treating and / or preventing the effects of dementia, comprising: an attenuation member comprising a plurality of fluid particles, the attenuation member having a low-profile configuration and a deployed configuration, the attenuation member being configured to be positioned along a circumference of an artery at a treatment site along a length of the artery when the attenuation member is in the deployed configuration; A device in which, when the attenuation member is in a deployed configuration and positioned at the treatment site, a wavefront traveling down the length of the artery redistributes at least a portion of the fluid particles along the length of the attenuation member, such that the inner diameter of the attenuation member increases at an axial position along the attenuation member that is aligned with the wavefront while the inner diameter of the attenuation member decreases at other axial positions along the attenuation member.

[0250] Example 78. The device described in Example 77, further comprising a structural element coupled to the damping member.

[0251] Example 79. A device described in Example 77 or Example 78, wherein in the deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.

[0252] Example 80. A device described in any one of Examples 77 to 79, wherein in the deployed state, the device has a preset spiral configuration.

[0253] Example 81. A device described in any one of Examples 77 to 80, wherein the damping member comprises a liquid.

[0254] Example 82. A device described in any one of Examples 77 to 81, wherein the damping member comprises a gas.

[0255] Example 83. A device described in any one of Examples 77 to 82, wherein the damping member comprises a gel.

[0256] Example 84. A device described in any one of Examples 77 to 83, wherein the attenuation member is configured to be positioned in juxtaposition with the outer surface of the arterial wall in the deployed configuration.

[0257] Example 85. A device described in any one of Examples 77 to 84, wherein the attenuation member is configured to be positioned around the arterial wall in the deployed configuration, such that the inner surface of the attenuation member comes into contact with blood flowing through the artery.

[0258] G. Examples 86-87: Methods for Treating and / or Preventing the Effects of Dementia Example 86. A method for treating and / or preventing the effects of dementia, comprising: 1. A method comprising: positioning an attenuation device in juxtaposition with at least one of the brachiocephalic trunk, the right common carotid artery, the left common carotid artery, the ascending aorta, and the aortic arch, the attenuation device having a resilient substantially tubular sidewall thereby absorbing pulsatile energy transmitted by blood flow through the at least one of the brachiocephalic trunk, the right common carotid artery, the left common carotid artery, the ascending aorta, and the aortic arch.

[0259] Example 87. A method for treating and / or preventing the effects of dementia, comprising: positioning an attenuation device in apposition with a wall of an artery that delivers blood to the brain, the attenuation device comprising a resilient generally tubular sidewall having an outer surface and a corrugated inner surface; A method, wherein at least one of the inner surface and the outer surface changes contour in response to pulse pressure waves in blood flowing through a blood vessel.

[0260] H. Example 88: Method for Treating at Least One of the Brachiocephalic Artery, the Right Common Carotid Artery, the Left Common Carotid Artery, the Ascending Aorta, and the Aortic Arch Example 88. A method for treating at least one of the brachiocephalic trunk, the right common carotid artery, the left common carotid artery, the ascending aorta, and the aortic arch, comprising: positioning an attenuation device in apposition with a vessel wall, the attenuation device comprising a resilient generally tubular sidewall; Expanding at least one of an inner diameter and an outer diameter of the attenuation device in response to an increase in pulse pressure; and contracting at least one of an inner diameter and an outer diameter of the attenuation device in response to the reduction in pulse pressure.

[0261] I. Examples 89-96: Methods of Treating Blood Vessels Example 89. A method for treating a blood vessel, comprising: Inserting a catheter into a blood vessel and directing a tip of the catheter to a desired blood vessel location; moving a distal anchor from within the catheter tip into the blood vessel; expanding the distal anchor such that a radially outer portion of the distal anchor engages an inner wall of the blood vessel; slightly withdrawing the catheter to move a proximal anchor from the tip of the catheter into the blood vessel; longitudinally positioning the proximal anchor at a desired location; expanding the proximal anchor such that a radially outer portion of the proximal anchor engages an inner wall of the blood vessel, wherein an elastically deformable member extends longitudinally between the proximal anchor and the distal anchor.

[0262] Example 90 The method of example 89, wherein moving the distal anchor comprises advancing the distal anchor from the tip of the catheter.

[0263] Example 91. The method of example 89 or example 90, wherein moving the distal anchor comprises withdrawing the tip of the catheter while the distal anchor remains in a generally constant longitudinal position within the blood vessel and exits the tip of the catheter.

[0264] Example 92. A method described in any one of Examples 89 to 91, wherein longitudinally positioning the proximal anchor includes applying a first tension to one or more threads frangibly secured to the proximal anchor.

[0265] Example 93. The method of Example 92, further comprising frangibly breaking the thread after expanding the proximal anchor by applying a second tension greater than the first tension.

[0266] Example 94. The method of Example 92, further comprising, after expanding the proximal anchor, disengaging a ring, latch, or clasp secured to the thread to detach the thread from the proximal anchor.

[0267] Example 95. The method of any one of Examples 89 to 94, further comprising imaging to determine the position of the proximal anchor and / or the distal anchor.

[0268] Example 96. A method of treating a blood vessel selected from the left common carotid artery, the right common carotid artery, or the brachiocephalic trunk, the carotid artery, a branch of any of the foregoing, and the ascending aorta, comprising: wrapping an elastically deformable material around the artery; and attaching a first edge of the elastically deformable material to an opposing second edge of the elastically deformable material such that an inner diameter of the elastically deformable material is smaller than an initial outer diameter of the artery during a systolic stage.

[0269] J. Examples 97-113: Methods for Treating Dementia Example 97. A method for treating dementia, comprising: positioning an attenuation device intravascularly within an artery at a treatment site, the attenuation device including an anchoring member coupled to a resilient tubular attenuation member defining a lumen therethrough; expanding the anchoring member and the dampening member from a low profile state to an expanded state such that at least the anchoring member is in apposition with the arterial wall at the treatment site; and varying a geometry of the damping member in response to pulse pressure waves in blood flowing through the damping member.

[0270] Example 98. The method of Example 97, further comprising reducing the magnitude of pulse pressure transmitted to a portion of the blood vessel distal to the attenuation device.

[0271] Example 99. The method of example 98, wherein reducing the magnitude of the pulse pressure comprises absorbing a portion of the pulsatile energy of blood flowing through the artery.

[0272] Example 100. A method according to any one of Examples 97 to 99, wherein changing the outer shape of the damping member includes increasing the inner diameter of the lumen of the damping member while the outer diameter of the damping member remains approximately constant.

[0273] Example 101. The method of any one of Examples 97 to 99, wherein changing the outer shape of the damping member includes increasing the inner and outer diameters of the lumen of the damping member.

[0274] Example 102. The method of any one of Examples 97 to 99, wherein changing the contour of the damping member includes decreasing the distance between the inner surface of the damping member and the outer surface of the damping member.

[0275] Example 103. The method of Examples 97-102, wherein intravascular positioning of the attenuation device comprises intravascular positioning of the attenuation device within the left common carotid artery at the treatment site.

[0276] Example 104. The method of any one of Examples 97 to 103, wherein intravascularly positioning the attenuation device comprises intravascularly positioning the attenuation device within the right common carotid artery at the treatment site.

[0277] Example 105. A method according to any one of Examples 97 to 104, wherein expanding the fixation member and expanding the damping member occur simultaneously.

[0278] Example 106. The method of any one of Examples 97-105, wherein expanding the fixation member includes expanding the fixation member using a balloon.

[0279] Example 107. The method of any one of Examples 97 to 105, wherein expanding the fixation member includes retracting a sheath to expose the fixation member and allowing the fixation member to self-expand.

[0280] Example 108. The method of any one of Examples 97 to 107, wherein expanding the attenuation member includes expanding the attenuation member using a balloon.

[0281] Example 109. A method according to any one of Examples 97 to 107, wherein expanding the attenuation member includes retracting a sheath to expose the attenuation member and allow the fixation member to self-expand.

[0282] Example 110. The method of any one of Examples 97 to 109, wherein expanding the fixation member expands the damping member.

[0283] Example 111. the attenuation device is a first attenuation device; the first attenuation device is positioned intravascularly at a first arterial location; The method of any one of Examples 97 to 110, wherein the method further comprises intravascularly positioning a second attenuation device at a second arterial location different from the first arterial location.

[0284] Example 112. The method of example 111, wherein the first arterial location is one of the left common carotid artery, the right common carotid artery, the external carotid artery, the internal carotid artery, and the ascending aorta, and the second arterial location is one of the left common carotid artery, the right common carotid artery, the external carotid artery, the internal carotid artery, and the ascending aorta.

[0285] Example 113 The method of example 111, wherein the first arterial location is the left common carotid artery and the second arterial location is the right common carotid artery.

[0286] K. Examples 114-115: Methods for Treating and / or Preventing the Effects of Dementia Example 114. A method for treating and / or preventing the effects of dementia, comprising: positioning an attenuation member along a length of the artery, the attenuation member including a mitigating substance; and redistributing at least a portion of the mitigation compound along a length of the dampening member in response to a pulse wave traveling through blood in the artery, thereby attenuating at least a portion of the energy of the pulse wave in the blood.

[0287] Example 115. A method for treating and / or preventing the effects of dementia, comprising: positioning an attenuation member along a length of the artery, the attenuation member comprising a plurality of fluid particles; and displacing a portion of the fluid particles away from an axial position along the damping member aligned with a wavefront of the pulse wave, thereby increasing an inner diameter of the damping member.

[0288] L. Examples 116 to 131: Devices for treating and / or preventing the progression of dementia Example 116. A device for treating and / or preventing the progression of dementia, comprising: a flexible, compliant attenuation member configured to be positioned intravascularly within an artery at a treatment site, the attenuation member being deformable between a low-profile state and an expanded state for delivery to the treatment site, the attenuation member including a generally tubular sidewall having (a) an outer surface, (b) an inner surface defining a lumen configured to direct blood flow, (c) a first end, (d) a second end along a length of the attenuation member opposite the first end, and (e) an attenuation region between the first end and the second end, the inner surface and the outer surface being spaced apart a greater distance at the attenuation region than at either the first end or the second end; a first anchoring member coupled to the first end of the attenuation member and a second anchoring member coupled to the second end of the attenuation member, wherein in a deployed state, the first anchoring member and the second anchoring member extend radially to a deployed diameter configured to contact a portion of the arterial wall at the treatment site, thereby securing the attenuation member to the treatment site, and the first anchoring member and the second anchoring member extend along only a portion of the length of the attenuation member, such that at least a portion of the attenuation region is exposed between the first anchoring member and the second anchoring member and allows the attenuation member to expand to a diameter larger than the deployed diameter.

[0289] Example 117. A device as described in Example 116, wherein the damping member is configured to deform in response to changes in blood / pulse pressure or pulse wave intensity / FCWI increase.

[0290] Example 118. A device described in Example 116 or Example 117, wherein at a position along the damping member coinciding with the leading edge of the pulse pressure wave, the distance between the inner surface and the outer surface of the damping member decreases in response to the pressure.

[0291] Example 119. A device described in any one of Examples 116 to 118, wherein the lumen of the attenuation member has an hourglass shape.

[0292] Example 120. A device described in any one of Examples 116 to 119, wherein the outer surface is approximately cylindrical and the inner surface is contoured.

[0293] Example 121. A device described in any one of Examples 116 to 120, wherein the first fixation member and the second fixation member are each an expandable stent.

[0294] Example 122. A device described in any one of Examples 116 to 120, wherein the first fixation member and the second fixation member are each an expandable mesh.

[0295] Example 123. A device described in any one of Examples 1 to 120, wherein the 116th fixation member and the second fixation member are each at least one of an expandable stent and an expandable mesh.

[0296] Example 124. A device described in any one of Examples 116 to 123, wherein the first fastening member and the second fastening member are each positioned around the circumference of the damping member.

[0297] Example 125. A device described in any one of Examples 116 to 124, wherein at least a portion of each of the first fastening member and the second fastening member is positioned within the damping member and extends through at least a portion of the thickness of the side wall.

[0298] Example 126. A device described in any one of Examples 116 to 125, wherein the damping region is a first damping region and the damping member includes multiple damping regions between the first end and the second end.

[0299] Example 127. A device described in any one of Examples 116 to 126, wherein at least one of the first fixation member and the second fixation member has a plurality of fixing devices extending radially outward from the outer surface of the attenuation device.

[0300] Example 128. A device described in any one of Examples 116 to 127, wherein the device is configured to be positioned at a treatment site within the left common carotid artery.

[0301] Example 129. A device described in any one of Examples 116 to 127, wherein the device is configured to be positioned at a treatment site in the right common carotid artery.

[0302] Example 130. A device described in any one of examples 116 to 129, wherein the device is configured to treat Alzheimer's disease.

[0303] Example 131. A device described in any one of examples 116 to 129, wherein the device is configured to reduce the occurrence of microbleeding in one or more branches of the artery downstream of the treatment site.

[0304] M. Examples 132-147: Devices for Treating Dementia Example 132. A device for treating dementia, comprising: an attenuation member configured for intravascular positioning within an artery at a treatment site and having a lumen configured to direct blood flow to distal vasculature, the attenuation member being deformable between a low-profile state for delivery to the treatment site and an expanded state, the attenuation member including an attenuation region having a pressure limiter that protrudes laterally inward into the lumen to distribute pressure downstream of the attenuation member as a pulse pressure wave propagates along the attenuation member during systole; and an anchoring member connected to the damping member, the anchoring member configured, in a deployed state, to extend outward to a deployed diameter and contact a portion of the vessel wall at the treatment site, thereby securing the damping member to the treatment site, the anchoring member extending along only a portion of the length of the damping member such that the damping region of the damping member is allowed to extend radially outward beyond the deployed diameter of the anchoring member.

[0305] Example 133. A device as described in Example 132, wherein the damping member is configured to deform in response to changes in blood / pulse pressure or pulse wave intensity / FCWI increase.

[0306] Example 134. A device described in Example 132 or 133, wherein at a position along the damping member coinciding with the leading edge of the pulse pressure wave, the distance between the inner surface and the outer surface of the damping member decreases in response to the pressure.

[0307] Example 135. A device described in any one of Examples 132 to 134, wherein the lumen of the attenuation member has an hourglass shape.

[0308] Example 136. A device described in any one of Examples 132 to 135, wherein the fixation member is an expandable stent.

[0309] Example 137. A device described in any one of Examples 132 to 136, wherein the fixation member is an expandable mesh.

[0310] Example 138. A device described in any one of Examples 132 to 137, wherein the fixation member is at least one of an expandable stent and an expandable mesh.

[0311] Example 139. A device described in any one of Examples 132 to 138, wherein the fastening member is positioned around the circumference of the damping member.

[0312] Example 140. A device described in any one of Examples 132 to 139, wherein at least a portion of the fastening member is positioned within the damping member and extends through at least a portion of the thickness of the side wall.

[0313] Example 141. A device described in any one of Examples 132 to 140, wherein the damping region is a first damping region and the damping member includes multiple damping regions between the first end and the second end.

[0314] Example 142. A device described in any one of Examples 132 to 141, wherein the fixation member includes a plurality of fixation devices extending radially outward from the outer surface of the attenuation device.

[0315] Example 143. A device described in any one of Examples 132 to 142, wherein the device is configured to be positioned at a treatment site within the left common carotid artery.

[0316] Example 144. A device described in any one of Examples 132 to 142, wherein the device is configured to be positioned at a treatment site in the right common carotid artery.

[0317] Example 145. A device described in any one of examples 132 to 144, wherein the device is configured to treat Alzheimer's disease.

[0318] Example 146. A device described in any one of examples 132 to 145, wherein the device is configured to reduce the occurrence of microbleeding in a portion of a blood vessel downstream of the treatment site.

[0319] Example 147. A device for treating dementia, comprising: a flexible, compliant attenuation member configured to be positioned intravascularly within an artery at a treatment site, the attenuation member being deformable between a low-profile state and an expanded state for delivery to the treatment site, the attenuation member including a generally tubular sidewall having (a) an outer surface, (b) an inner surface defining a lumen configured to direct blood flow, (c) a first end, (d) a second end along a length of the attenuation member opposite the first end, and (e) an attenuation region between the first end and the second end, the inner surface and the outer surface being spaced apart a greater distance at the attenuation region than at either the first end or the second end; a first anchoring member coupled to the first end of the attenuation member and a second anchoring member coupled to the second end of the attenuation member, the first anchoring member and the second anchoring member extending radially to a deployed diameter configured to contact a portion of the vessel wall at the treatment site in a deployed state, thereby anchoring the attenuation member at the treatment site; A device in which as blood flows through the damping member during systole, the damping member absorbs a portion of the blood's pulsating energy, thereby reducing the magnitude of pulse pressure transmitted to a portion of the blood vessel distal to the attenuation device.

[0320] N. Examples 148-154: Devices for treating blood vessels Example 148. A device for treating a blood vessel, comprising: an anchoring system having a first portion and a second portion spaced apart in a first direction from the first portion; a cushioning member positioned between the first and second portions of the fixation system such that movement of a portion of the cushioning member in a second direction perpendicular to the first direction is not restricted by the fixation system, the cushioning member being configured to absorb pulsating energy transmitted by blood flowing through the blood vessel.

[0321] Example 149. A device as described in Example 148, wherein the cushioning member is elastically deformable and configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the increase in blood pressure / pulse pressure or pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0322] Example 150. A device for treating a blood vessel, comprising: an intravascular cushioning device having a proximal anchor and a distal anchor spaced from the proximal anchor, the proximal anchor and the distal anchor each configured to abut an inner wall of the aorta; an elastically deformable member extending between the proximal anchor and the distal anchor; The device, wherein the elastically deformable member is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0323] Example 151. A device as described in Example 150, wherein a portion of the elastically deformable membrane positioned longitudinally between the proximal anchor and the distal anchor defines an area of ​​reduced internal cross-sectional area compared to the proximal anchor and the distal anchor when the elastically deformable membrane is radially relaxed.

[0324] Example 152. A device described in Example 150 or Example 151, wherein the proximal anchor and the distal anchor are each radially expandable between a first diameter before deployment and a second diameter after deployment.

[0325] Example 153. A device described in any one of Examples 150 to 152, further comprising one or more threads fixed to the proximal anchor.

[0326] Example 154. The device of example 153, wherein each thread is secured to an eyelet.

[0327] O. Examples 155-160: Devices for treating an artery selected from the left common carotid artery, the right common carotid artery, the brachiocephalic artery, the ascending aorta, the internal carotid artery, or the abdominal aorta Example 155. A device for treating an artery selected from the left common carotid artery, the right common carotid artery, the brachiocephalic trunk, the ascending aorta, the internal carotid artery, or the abdominal aorta, comprising: a wrap made from an elastically deformable material; and an engagement formation adapted to secure two opposing edges of the wrap around the artery; The device, wherein the elastically deformable material is configured to radially expand during a systolic phase and radially contract during a diastolic phase.

[0328] Example 156. A device as described in Example 155, wherein the wrap completely or substantially completely surrounds the artery over a portion of the length of the artery when the wrap is positioned around the artery.

[0329] Example 157. A device as described in Example 155, wherein the engagement formation comprises a suture and / or a staple.

[0330] Example 158. A device as described in Example 155, wherein the engagement forming portion comprises a Ziploc (registered trademark).

[0331] Example 159. A device for treating the left common carotid artery, the right common carotid artery, the brachiocephalic trunk, or the ascending aorta, comprising: a proximal anchor configured to be wrapped around the artery; a distal anchor configured to be wrapped around the artery and longitudinally spaced apart from the proximal anchor; a helical band adapted to be wrapped around the artery, the helical band having a first end securable to the proximal anchor and an opposing second end securable to the distal anchor, the helical band adapted to radially expand during a systolic phase and radially contract during a diastolic phase.

[0332] Example 160. A device as described in Example 159, wherein the first end of the spiral band is fixed to the proximal anchor and the second end of the spiral band is fixed to the distal anchor.

[0333] P. Examples 161-214: Devices for treating and / or preventing the effects of dementia Example 161. A device for treating and / or preventing the effects of dementia, comprising: A device comprising: a damping member having a deformable, generally tubular sidewall having an outer surface and a longitudinally contoured inner surface, the sidewall configured to be positioned in juxtaposition with a blood vessel wall to absorb pulsatile energy transmitted by blood flowing through the vessel.

[0334] Example 162. A device as described in Example 161, wherein the attenuation member is configured to be positioned in juxtaposition with at least one of the left common carotid artery, the right common carotid artery, and the brachiocephalic artery.

[0335] Example 163. A device as described in Example 161, wherein the attenuation member is configured to be positioned in juxtaposition with the ascending aorta.

[0336] Example 164. A device described in any one of Examples 161 to 163, wherein the attenuation member is configured to be positioned in juxtaposition with the inner surface of the vascular wall.

[0337] Example 165. A device described in any one of Examples 161 to 163, wherein the attenuation member is configured to be positioned in juxtaposition with the outer surface of the vascular wall.

[0338] Example 166. A device described in any one of Examples 161 to 165, wherein the side wall has an inner diameter, and when the damping member is in the deployed state, the inner diameter increases in the axial direction and then decreases.

[0339] Example 167. A device described in any one of Examples 161 to 166, wherein the cross-sectional area decreases and then increases in the longitudinal direction.

[0340] Example 168. A device described in any one of Examples 161 to 167, wherein the outer surface has an approximately cylindrical shape.

[0341] Example 169. A device described in any one of Examples 161 to 167, wherein the outer surface has an undulating shape.

[0342] Example 170. A device described in any one of Examples 161 to 169, further comprising an anchoring member connected to the damping member and axially aligned with only a portion of the damping member, the anchoring member configured to engage the vascular wall and secure the damping member to the vascular wall.

[0343] Example 171. The fastening member is a first fastening member, and the device further comprises a second fastening member coupled to the damping member, the second fastening member comprising: in axial alignment with only a portion of the damping member; and The device of Example 170, wherein the damping member is spaced apart from the first fastening member along the longitudinal axis of the damping member.

[0344] Example 172. A device described in any one of Examples 161 to 171, wherein the attenuation member does not restrict the diameter of the blood vessel wall when the attenuation member is positioned adjacent to the blood vessel wall.

[0345] Example 173. A device for treating and / or preventing the effects of dementia, comprising: 1. A device comprising: an elastic member configured to abut an arterial wall and form a generally tubular structure having an inner diameter, an outer diameter, an outer surface, and a contoured inner surface, at least one of the outer diameter and the inner diameter increasing and decreasing, respectively, in response to increases and decreases in pulse pressure within the blood vessel.

[0346] Example 174. A device as described in Example 173, wherein the elastic member is configured to be positioned in juxtaposition with at least one of the left common carotid artery, the right common carotid artery, and the brachiocephalic artery.

[0347] Example 175. A device as described in Example 173, wherein the elastic member is configured to be positioned in juxtaposition with the ascending aorta.

[0348] Example 176. A device described in any one of Examples 173 to 175, wherein the elastic member is configured to be positioned in juxtaposition with the inner surface of the vascular wall.

[0349] Example 177. A device described in any one of Examples 173 to 175, wherein the elastic member is configured to be positioned in juxtaposition with the outer surface of the vascular wall.

[0350] Example 178. A device described in any one of Examples 173 to 177, wherein the side wall has an inner diameter, and when the elastic member is in an expanded state, the inner diameter increases in the axial direction and then decreases.

[0351] Example 179. A device described in any one of Examples 173 to 178, wherein the cross-sectional area decreases and then increases in the longitudinal direction.

[0352] Example 180. A device described in any one of Examples 173 to 179, wherein the outer surface has a generally cylindrical shape.

[0353] Example 181. A device described in any one of Examples 173 to 179, wherein the outer surface has an undulating shape.

[0354] Example 182. A device described in any one of Examples 173 to 181, further comprising an anchoring member connected to the elastic member and axially aligned with only a portion of the elastic member, the anchoring member configured to engage the vascular wall and secure the elastic member to the vascular wall.

[0355] Example 183. The fastening member is a first fastening member, and the device further comprises a second fastening member coupled to the elastic member, the second fastening member comprising: in axial alignment with only a portion of the resilient member; and The device of Example 182, wherein the elastic member is spaced apart from the first fastening member along the longitudinal axis of the elastic member.

[0356] Example 184. A device described in any one of Examples 173 to 183, wherein the elastic member does not restrict the diameter of the blood vessel wall when the elastic member is positioned adjacent to the blood vessel wall.

[0357] Example 185. A device described in any one of Examples 173 to 184, wherein the damping member or the elastic member has a thin state and an expanded state.

[0358] Example 186. The device described in Example 185, wherein the deployed state is for delivery to a treatment site in a blood vessel wall.

[0359] Example 187. A device described in Example 185 or 186, wherein the damping member or the elastic member has a first smaller outer diameter when in the thin state and a second larger diameter when in the expanded state.

[0360] Example 188. A device for treating and / or preventing the effects of dementia, comprising: A device comprising: a damping member containing a mitigation material, the damping member forming a generally tubular structure having an axis, the mitigation material being capable of moving axially relative to the tubular structure, the damping member being configured to be positioned along the circumference of an artery such that when a pulse wave traveling through the artery applies stress to a first axial location along the length of the tubular structure, at least a portion of the mitigation material moves away from the first location to a second axial location along the length of the tubular structure.

[0361] Example 189. A device as described in Example 188, wherein the mitigation substance comprises a volume of fluid and / or gel containing particles contained within a flexible member, and the particles are capable of moving axially within the flexible member relative to the tubular structure.

[0362] Example 190. A device as described in Example 189, wherein the flexible member is capable of radially deforming relative to the tubular structure at at least some locations along the length of the tubular structure.

[0363] Example 191. A device described in any one of Examples 188 to 190, further comprising a structural element connected to the damping member.

[0364] Example 192. A device described in any one of Examples 188 to 191, wherein in a deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.

[0365] Example 193. A device as described in Example 192, comprising a break along its length to allow the attenuation member to be fitted around the portion of the circumference of the artery.

[0366] Example 194. A device as described in Example 193, further comprising cooperating sealing devices positioned on or near opposing edges of the break to enable the edges to be joined together when the attenuation member is fitted around the portion of the circumference of the artery.

[0367] Example 195. A device described in any one of Examples 188 to 194, wherein in a deployed state, the device has a preset spiral configuration.

[0368] Example 196. A device described in any one of Examples 188 to 195, wherein the damping member comprises a liquid.

[0369] Example 197. A device described in any one of Examples 188 to 196, wherein the damping member comprises a gas.

[0370] Example 198. A device described in any one of Examples 188 to 197, wherein the damping member comprises a gel.

[0371] Example 199. A device described in any one of Examples 188 to 198, wherein the attenuation member is configured to be positioned in juxtaposition with the outer surface of the arterial wall in the deployed configuration.

[0372] Example 200. A device described in any one of Examples 188 to 199, wherein the attenuation member is configured to be positioned around the arterial wall in a deployed configuration, such that the inner surface of the attenuation member comes into contact with blood flowing through the artery.

[0373] Example 201. A device for treating and / or preventing the effects of dementia, comprising: the fluid particles are capable of moving axially along at least a portion of a length of the attenuation structure, the attenuation member being configured to be positioned along a circumference of the artery at a treatment site along the length of the artery; A device in which, when the attenuation member is in a deployed configuration and positioned at the treatment site, a wavefront traveling down the length of the artery redistributes at least a portion of the fluid particles along the length of the attenuation member, such that the inner diameter of the attenuation member increases at an axial position along the attenuation member that is aligned with the wavefront while the inner diameter of the attenuation member decreases at other axial positions along the attenuation member.

[0374] Example 202. A device as described in Example 201, wherein the fluid particles are contained within a flexible member, and the particles can move within the flexible member along the length of the damping member.

[0375] Example 203. A device as described in Example 202, wherein the flexible member is capable of radially deforming relative to the damping member at at least some locations along the length of the damping member.

[0376] Example 204. A device described in any one of Examples 201 to 203, further comprising a structural element coupled to the damping member.

[0377] Example 205. A device described in any one of Examples 201 to 204, wherein in a deployed state, the damping member is configured to wrap around at least a portion of the circumference of the artery.

[0378] Example 206. A device as described in Example 205, comprising a break along its length to allow the attenuation member to be fitted around the portion of the circumference of the artery.

[0379] Example 207. A device as described in Example 206, further comprising cooperating sealing devices positioned on or near opposing edges of the break to enable the edges to be joined together when the attenuation member is fitted around the portion of the circumference of the artery.

[0380] Example 208. A device described in any one of Examples 201 to 207, wherein in the deployed state, the device has a preset spiral configuration.

[0381] Example 209. A device described in any one of Examples 201 to 208, wherein the damping member comprises a liquid.

[0382] Example 210. A device described in any one of Examples 201 to 209, wherein the damping member comprises a gas.

[0383] Example 211. A device described in any one of Examples 201 to 210, wherein the damping member comprises a gel.

[0384] Example 212. A device described in any one of Examples 201 to 211, wherein the attenuation member is configured to be positioned in juxtaposition with the outer surface of the arterial wall in the deployed configuration.

[0385] Example 213. A device described in any one of Examples 201 to 212, wherein the attenuation member is configured to be positioned around the arterial wall in the deployed configuration, such that the inner surface of the attenuation member comes into contact with blood flowing through the artery.

[0386] Example 214. A device described in any one of Examples 201 to 213, wherein the damping member has a low-profile configuration and an expanded configuration.

[0387] Q. Examples 215-401: Methods for Treating and / or Preventing One or More Effects of a Condition Example 215. A method for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising: A device for treating and / or preventing one or more of the effects of the condition, comprising: A device configured to be placed in apposition to a blood vessel, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; and providing a therapy in combination with the device to treat or delay one or more effects of the condition.

[0388] Example 216. The method of example 215, wherein the therapy is an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0389] Example 217. The method of Example 216, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

[0390] Example 218 The method of example 216, wherein the MMP inhibitor is doxycycline or dexamethasone.

[0391] Example 219. The method of example 216, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

[0392] Example 220. The method of any one of Examples 215-219, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents and / or reduces expression and / or accumulation of β-amyloid protein in the brain of the subject, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents neuronal dysregulation / damage and / or death, prevents blood-brain barrier dysregulation and / or damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

[0393] Example 221. The method of any one of examples 215-220, wherein the therapy is provided in a first dosage amount that is less than a second dosage amount provided in the absence of the device.

[0394] Example 222. The method of any one of examples 215-235, wherein the therapy is provided at a first dosing regimen that is less than a second dosing regimen that is provided in the absence of the device.

[0395] Example 223. The method of any one of examples 215-236, wherein the therapy is provided via a first route that is different from a second route that is provided in the absence of the device.

[0396] Example 224. The method of any one of Examples 215-235, wherein said therapy is provided by administering said therapy to said subject in need of said therapy.

[0397] Example 225. The method of any one of Examples 215 to 222, wherein the condition is neurodegeneration.

[0398] Example 226. The method of example 225, wherein the neurodegeneration further comprises Alzheimer's disease, dementia, and / or cognitive impairment.

[0399] Example 227 The method of any one of Examples 215-226, wherein the device has a low-profile state and an expanded state, and when in the expanded state, the sidewall is generally tubular.

[0400] Example 228. The method of any one of Examples 215 to 227, wherein the mitigating substance is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0401] Example 229. The method of Example 228, wherein the flexible damping member is positioned in juxtaposition with the blood vessel and applies stress to a first location along the length of the tubular structure when a pulse wave travels through the blood vessel.

[0402] Example 230. The method of example 229, wherein after stress is applied to the first location, at least a portion of the mitigation material migrates longitudinally and / or radially along the length of the tubular structure.

[0403] Example 231. The method of Example 229, wherein at least a portion of the mitigation material is configured to move longitudinally and / or radially from a first position within a first deformable portion of the flexible damping member to a second position within the first deformable portion after stress is applied to the first position.

[0404] Example 232. The method of Example 229, further configured to move at least a portion of the mitigation material longitudinally and / or radially from the first location to a third location within the second deformable portion of the flexible damping member after stress is applied to the first location.

[0405] Example 233. The method according to any one of examples 215 to 232, wherein the inner and / or outer surface has a generally cylindrical shape or a longitudinally undulating shape.

[0406] Example 234. A method according to any one of Examples 215 to 233, wherein the flexible damping member is further configured to be positioned around at least a portion of the circumference of the wall of the blood vessel, such that when a pulse wave traveling through the blood vessel exerts stress on a first region of the damping member, at least a portion of the mitigating substance moves away from the first region to a second region of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0407] Example 235. The method of any one of Examples 215 to 234, wherein the device is further configured to be deployed within the lumen of the blood vessel, such that the outer surface of the fixation member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the side wall is in contact with blood flowing through the blood vessel lumen.

[0408] Example 236. The method described in Example 235, wherein when the device is deployed within the vascular lumen and a pulse wave traveling through the blood vessel applies stress to a third position of the damping member, at least a portion of the mitigation substance moves away from the third position to a fourth position of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0409] Example 237. A method for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising: providing a device for treating and / or preventing one or more effects of the condition, the device being configured to be placed in apposition to a blood vessel, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; A method wherein a therapy that treats or delays one or more of the effects of the condition has previously been provided to the subject in need thereof.

[0410] Example 238. The method of example 237, wherein the therapy is an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0411] Example 239. The method of Example 238, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

[0412] Example 240 The method of example 238, wherein the MMP inhibitor is doxycycline or dexamethasone.

[0413] Example 241 The method of example 238, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

[0414] Example 241. The method of any one of Examples 237-240, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents and / or reduces expression and / or accumulation of β-amyloid protein in the brain of the subject, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents or reduces neuronal dysregulation / damage and / or death, prevents or reduces blood-brain barrier dysregulation or permeability / damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

[0415] Example 242. The method of any one of examples 237-241, wherein the therapy is provided in a first dosage amount that is less than a second dosage amount provided in the absence of the device.

[0416] Example 243. The method of any one of examples 237-242, wherein the therapy is provided at a first dosing regimen that is less than a second dosing regimen that is provided in the absence of the device.

[0417] Example 244. The method of any one of examples 237-243, wherein the therapy is provided via a first route that is different from a second route that is provided in the absence of the device.

[0418] Example 245. The method of any one of Examples 237-244, wherein said therapy is provided by administering said therapy to said subject in need of said therapy.

[0419] Example 246. The method of any one of Examples 237 to 244, wherein the condition is neurodegeneration.

[0420] Example 247. The method of Example 246, wherein the neurodegeneration further comprises Alzheimer's disease, dementia, and / or cognitive impairment.

[0421] Example 248. The method of any one of Examples 237 to 247, wherein the device has a low-profile state and an expanded state, and when in the expanded state, the sidewall is generally tubular.

[0422] Example 249. A method according to any one of Examples 237 to 248, wherein the mitigating substance is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0423] Example 250. The method of Example 249, wherein the flexible damping member is positioned in juxtaposition with the blood vessel and applies stress to a first location along the length of the tubular structure when a pulse wave travels through the blood vessel.

[0424] Example 251. The method of Example 250, wherein after stress is applied to the first location, at least a portion of the mitigation material migrates longitudinally and / or radially along the length of the tubular structure.

[0425] Example 252. The method of Example 250, wherein at least a portion of the mitigation material is configured to move longitudinally and / or radially from a first position within a first deformable portion of the flexible damping member to a second position within the first deformable portion after stress is applied to the first position.

[0426] Example 253. The method of Example 250, further configured to move at least a portion of the mitigation material longitudinally and / or radially from the first location to a third location within the second deformable portion of the flexible damping member after stress is applied to the first location.

[0427] Example 254. The method according to any one of examples 237 to 253, wherein the inner and / or outer surface has a generally cylindrical shape or a longitudinally undulating shape.

[0428] Example 255. A method according to any one of Examples 237 to 254, wherein the flexible damping member is further configured to be positioned around at least a portion of the circumference of the wall of the blood vessel, such that when a pulse wave traveling through the blood vessel applies stress to a first region of the damping member, at least a portion of the mitigating substance moves away from the first region to a second region of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0429] Example 256. The method of any one of Examples 237 to 255, wherein the device is further configured to be deployed within the lumen of the blood vessel, such that the outer surface of the fixation member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the side wall is in contact with blood flowing through the blood vessel lumen.

[0430] Example 257. The method of Example 256, wherein when the device is deployed within the vascular lumen and a pulse wave traveling through the blood vessel applies stress to a third position of the damping member, at least a portion of the mitigation substance moves away from the third position to a fourth position of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0431] Example 258. A method for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising: providing a therapy for treating and / or preventing one or more effects of the condition to a subject in need thereof, the subject having previously been provided with a device that treats or delays one or more effects of the condition and that is placed in apposition to a blood vessel, the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; and a mitigation material disposed within the one or more at least partially deformable portions of the side wall, the mitigation material being configured to move longitudinally and / or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel.

[0432] Example 259. The method of example 258, wherein the therapy is an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0433] Example 260. The method of Example 259, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

[0434] Example 261 The method of Example 260, wherein the MMP inhibitor is doxycycline or dexamethasone.

[0435] Example 262. The method of example 260, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

[0436] Example 263. The method of any one of Examples 258-262, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents and / or reduces expression and / or accumulation of β-amyloid protein in the brain of the subject, reduces inflammation, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents or reduces neuronal dysregulation / damage and / or death, prevents or reduces blood-brain barrier dysregulation or permeability / damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

[0437] Example 264. The method of any one of examples 258-263, wherein the therapy is provided in a first dosage amount that is less than a second dosage amount provided in the absence of the device.

[0438] Example 265. The method of any one of Examples 258-264, wherein the therapy is provided at a first dosing regimen that is less than a second dosing regimen that is provided in the absence of the device.

[0439] Example 266. The method of any one of examples 258-265, wherein the therapy is provided via a first route that is different from a second route that is provided in the absence of the device.

[0440] Example 267. The method of any one of Examples 258-266, wherein said therapy is provided by administering said therapy to said subject in need of said therapy.

[0441] Example 268. The method of any one of Examples 258 to 267, wherein the condition is neurodegeneration.

[0442] Example 269. The method of Example 268, wherein the neurodegeneration further comprises Alzheimer's disease, dementia, and / or cognitive impairment.

[0443] Example 270. The method of any one of Examples 258 to 269, wherein the device has a low-profile state and an expanded state, and when in the expanded state, the side wall is generally tubular.

[0444] Example 271. A method according to any one of Examples 258 to 270, wherein the mitigating substance is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0445] Example 272. The method of Example 271, wherein the flexible damping member is positioned in juxtaposition with the blood vessel and applies stress to a first location along the length of the tubular structure when a pulse wave travels through the blood vessel.

[0446] Example 273. The method of example 272, wherein after stress is applied to the first location, at least a portion of the mitigation material migrates longitudinally and / or radially along the length of the tubular structure.

[0447] Example 274. The method described in Example 273, wherein at least a portion of the mitigation material is configured to move longitudinally and / or radially from a first position within a first deformable portion of the flexible damping member to a second position within the first deformable portion after stress is applied to the first position.

[0448] Example 275. The method of Example 274, further configured to move at least a portion of the mitigation material longitudinally and / or radially from the first location to a third location within the second deformable portion of the flexible damping member after stress is applied to the first location.

[0449] Example 276. The method according to any one of examples 258 to 275, wherein the inner and / or outer surface has a generally cylindrical shape or a longitudinally undulating shape.

[0450] Example 277. A method according to any one of Examples 258 to 276, wherein the flexible damping member is further configured to be positioned around at least a portion of the circumference of the wall of the blood vessel, such that when a pulse wave traveling through the blood vessel applies stress to a first region of the damping member, at least a portion of the mitigating substance moves away from the first region to a second region of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0451] Example 278. The method of any one of Examples 258 to 277, wherein the device is further configured to be deployed within the lumen of the blood vessel, such that the outer surface of the fixation member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the side wall is in contact with blood flowing through the blood vessel lumen.

[0452] Example 279. The method described in Example 278, wherein when the device is deployed within the vascular lumen and a pulse wave traveling through the blood vessel applies stress to a third position of the damping member, at least a portion of the mitigation substance moves away from the third position to a fourth position of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0453] Example 280. A system for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising: an effective amount of a therapy for treating and / or preventing one or more of the effects of the condition; and a device for treating and / or preventing one or more effects of the condition; The device: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; and a mitigation material disposed within the one or more at least partially deformable portions of the side wall, the mitigation material being configured to move longitudinally and / or radially within one partially deformable portion in response to pulsatile blood flow within the blood vessel.

[0454] Example 281. The EDG receptor family modulator, MMP inhibitor, or senolytic agent, or a combination thereof, of the system described in Example 280.

[0455] Example 282. The system of Example 281, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

[0456] Example 283. The system of Example 282, wherein the MMP inhibitor is doxycycline or dexamethasone.

[0457] Example 284. The system of example 282, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

[0458] Example 285. The method of any one of Examples 280 to 284, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents and / or reduces expression and / or accumulation of β-amyloid protein in the brain of the subject, reduces inflammation, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents or reduces neuronal dysregulation / damage and / or death, prevents or reduces blood-brain barrier dysregulation or permeability / damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

[0459] Example 286. A system described in any one of Examples 280 to 285, wherein the therapy is provided in a first dosage amount that is less than a second dosage amount provided in the absence of the device.

[0460] Example 287. A system described in any one of Examples 280 to 286, wherein the therapy is provided at a first dosing regimen that is less than a second dosing regimen provided in the absence of the device.

[0461] Example 288. A system described in any one of Examples 280 to 287, wherein the therapy is provided via a first route that is different from a second route that is provided in the absence of the device.

[0462] Example 289. A system described in any one of Examples 280 to 288, wherein the therapy is provided by administering the therapy to the subject in need of the therapy.

[0463] Example 290. A system described in any one of Examples 280 to 289, wherein the condition is neurodegeneration.

[0464] Example 291. The system described in Example 290, wherein the neurodegeneration further includes Alzheimer's disease, dementia, and / or cognitive impairment.

[0465] Example 292. A system described in any one of Examples 280 to 291, wherein the inner and / or outer surface has a generally cylindrical shape or a longitudinally undulating shape.

[0466] Example 293. A system described in any one of Examples 280 to 292, wherein the device has a thin state and an expanded state, and when in the expanded state, the side wall is approximately tubular.

[0467] Example 294. A system described in any one of Examples 280 to 293, wherein the mitigation substance is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the increase in blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0468] Example 295. A system as described in Example 294, positioned in juxtaposition with the blood vessel and wherein the flexible damping member applies stress to a first location along the length of the tubular structure when a pulse wave travels through the blood vessel.

[0469] Example 296. The system described in Example 295, wherein after stress is applied to the first location, at least a portion of the mitigation material moves longitudinally and / or radially along the length of the tubular structure.

[0470] Example 297. The system described in Example 295, wherein at least a portion of the mitigation material is configured to move longitudinally and / or radially from a first position within a first deformable portion of the flexible damping member to a second position within the first deformable portion after stress is applied to the first position.

[0471] Example 298. The system described in Example 295, further configured to move at least a portion of the mitigation material longitudinally and / or radially from the first location to a third location within the second deformable portion of the flexible damping member after stress is applied to the first location.

[0472] Example 299. A system described in any one of Examples 280 to 298, wherein the flexible damping member is further configured to be positioned around at least a portion of the circumference of the wall of the blood vessel, such that when a pulse wave traveling through the blood vessel applies stress to a first region of the damping member, at least a portion of the mitigating substance moves away from the first region to a second region of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0473] Example 300. A system described in any one of Examples 280 to 299, wherein the device is further configured to be deployed within the lumen of the blood vessel such that the outer surface of the fixation member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the side wall is in contact with blood flowing through the blood vessel lumen.

[0474] Example 301. The system described in Example 300, wherein when the device is deployed within the vascular lumen and a pulse wave traveling through the blood vessel applies stress to a third position of the damping member, at least a portion of the mitigation material moves away from the third position to a fourth position of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0475] Example 302. A system for treating and / or preventing one or more effects of a condition in a subject in need thereof, comprising: an effective amount of a therapy for treating and / or preventing one or more of the effects of the condition; and a device for treating and / or preventing one or more effects of the condition; The device: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions configured to move longitudinally and / or radially within the one or more at least partially deformable portions in response to pulsatile blood flow within the blood vessel; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; the effective amount of the therapy for treating and / or preventing one or more effects of the condition is delivered by one or more of the at least partially deformable portions of the device; When the one or more at least partially deformable portions are at least partially deformed, the effective amount of a therapy for treating and / or preventing one or more effects of the condition is released from the device.

[0476] Example 303. The system of Example 302, wherein the effective amount of the therapy further comprises a first effective amount of the therapy and a second effective amount of the therapy.

[0477] Example 304. The system described in Example 303, wherein the second effective amount of the therapy is greater than the first effective amount of the therapy.

[0478] Example 305. A system as described in Example 304, wherein the one or more at least partially deformable portions at least partially deform to a first deformation degree in response to a first pulsatile blood flow in the blood vessel.

[0479] Example 306. The system described in Example 305, wherein the one or more at least partially deformable portions at least partially deform to a second deformation degree in response to a second pulsatile blood flow in the blood vessel.

[0480] Example 307. A system as described in Example 306, wherein the second degree of deformation is greater than the first degree of deformation.

[0481] Example 308. The system described in Example 307, wherein the first effective amount of the therapy is released from the one or more at least partially deformable portions in response to the first degree of deformation.

[0482] Example 309. The system described in Example 308, wherein the second effective amount of the therapy is released from the one or more at least partially deformable portions in response to the second degree of deformation.

[0483] Example 310. The system of any one of Examples 302 to 309, wherein the therapy is an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

[0484] Example 311. The system of Example 310, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

[0485] Example 312 The system described in Example 310, wherein the MMP inhibitor is doxycycline or dexamethasone.

[0486] Example 313 The system of example 310, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

[0487] Example 314. The method of any one of Examples 359-384, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents and / or reduces expression and / or accumulation of β-amyloid protein in the brain of the subject, reduces inflammation, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents or reduces neuronal dysregulation / damage and / or death, prevents or reduces blood-brain barrier dysregulation or permeability / damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

[0488] Example 315. A system described in any one of examples 359 to 385, wherein the therapy is provided at a first dosage that is less than a second dosage provided in the absence of the device.

[0489] Example 316. A system described in any one of examples 359 to 386, wherein the therapy is provided at a first dosing regimen that is less than a second dosing regimen provided in the absence of the device.

[0490] Example 317. A system described in any one of examples 359 to 387, wherein the therapy is provided via a first route that is different from a second route that is provided in the absence of the device.

[0491] Example 318. A system described in any one of Examples 359 to 388, wherein the therapy is provided by administering the therapy to the subject in need of the therapy.

[0492] Example 319. A system described in any one of Examples 359 to 389, wherein the condition is neurodegeneration.

[0493] Example 320. The system described in Example 390, wherein the neurodegeneration further includes Alzheimer's disease, dementia, and / or cognitive impairment.

[0494] Example 321. A system described in any one of Examples 359 to 391, wherein the inner and / or outer surface has a generally cylindrical shape or a longitudinally undulating shape.

[0495] Example 322. A system described in any one of examples 359 to 392, wherein the device has a thin state and an expanded state, and when in the expanded state, the side wall is approximately tubular.

[0496] Example 323. A system described in any one of Examples 359 to 393, wherein the mitigation substance is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0497] Example 324. A system as described in Example 394, positioned in juxtaposition with the blood vessel and wherein the flexible damping member applies stress to a first location along the length of the tubular structure when a pulse wave travels through the blood vessel.

[0498] Example 325. A system as described in Example 395, wherein after stress is applied to the first location, at least a portion of the mitigation material moves longitudinally and / or radially along the length of the tubular structure.

[0499] Example 326. The system described in Example 395, wherein at least a portion of the mitigation material is configured to move longitudinally and / or radially from a first position within a first deformable portion of the flexible damping member to a second position within the first deformable portion after stress is applied to the first position.

[0500] Example 327. The system described in Example 395, further configured to move at least a portion of the mitigation material longitudinally and / or radially from the first location to a third location within the second deformable portion of the flexible damping member after stress is applied to the first location.

[0501] Example 328. A system described in any one of Examples 359 to 398, wherein the flexible damping member is further configured to be positioned around at least a portion of the circumference of the wall of the blood vessel, such that when a pulse wave traveling through the blood vessel applies stress to a first region of the damping member, at least a portion of the mitigating substance moves away from the first region to a second region of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0502] Example 329. A system described in any one of Examples 359 to 399, wherein the device is further configured to be deployed within the lumen of the blood vessel such that the outer surface of the fixation member is juxtaposed with the lumen of the blood vessel wall and the outer surface of the side wall is in contact with blood flowing through the blood vessel lumen.

[0503] Example 330. The system described in Example 400, wherein when the device is deployed within the vascular lumen and a pulse wave traveling through the blood vessel applies stress to a third position of the damping member, at least a portion of the mitigation material moves away from the third position to a fourth position of the damping member, thereby causing the damping member to absorb at least a portion of the energy of the pulse wave, thereby reducing the stress on the blood vessel wall distal to the device.

[0504] R. Examples 331-349: Methods for Treating a Patient Having a Condition Example 331. A method for treating a patient having a condition, comprising: (a) the patient has elevated pulse pressure, elevated pulse wave intensity / FCWI and a history of microbleeds, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating or cerebrospinal fluid (CSF) cytokine, elevated levels of reactive oxygen species, or a combination thereof; (i) obtaining or having been obtained information indicating that the patient has the elevated pulse pressure, the elevated pulse wave intensity / FCWI and has previously had symptoms of microbleeds, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated circulating or CSF cytokine level, reactive oxygen species, or a combination thereof, and / or has previously been diagnosed with microbleeds, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated circulating or CSF cytokine level, reactive oxygen species, or a combination thereof; and / or (ii) monitoring or having been monitored for symptoms of the pulse pressure elevation, the pulse wave intensity / FCWI elevation, and microbleeds, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating cytokine, elevated reactive oxygen species, or a combination thereof; (b) the patient has previously had symptoms of microbleeds, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated level of a circulating cytokine, increased reactive oxygen species, or a combination thereof; the patient has previously been diagnosed with microbleeds, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated level of a circulating cytokine, increased reactive oxygen species, or a combination thereof; and / or the patient has been monitored for symptoms of microbleeds, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, at least one elevated level of a circulating cytokine, or a combination thereof; (i) providing to the patient an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof; (ii) providing a device for treating and / or preventing one or more effects of the condition, The device: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions configured to move longitudinally and / or radially within the one or more at least partially deformable portions in response to pulsatile blood flow within the blood vessel; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; (c) providing said device for treating and / or preventing one or more effects of said condition if the patient has not previously been diagnosed with microhemorrhage, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating cytokine, increased reactive oxygen species, or a combination thereof, if the patient has not previously been diagnosed with microhemorrhage, blood-brain barrier dysregulation and / or increased permeability, systemic inflammation, blood-brain barrier inflammation, neuroinflammation, elevated levels of at least one circulating cytokine, increased reactive oxygen species, or a combination thereof.

[0505] Example 332. The method of example 331, wherein the pulse pressure increase is a pulse pressure of at least 50 mmHg.

[0506] Example 333. The method of example 331 or example 332, wherein the increase in the level of at least one circulating cytokine in (b) is at least about 5% higher than the level in (c).

[0507] Example 334. The method of any one of Examples 331 to 333, wherein the at least one cytokine is selected from the group consisting of VCAM-1, ICAM-1, TNFα, TGF-β, IL-6, IL-8, IL-1β, IL-12, and NF-κB.

[0508] Example 335 The method of Example 331, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

[0509] Example 336 The method of example 331, wherein the MMP inhibitor is doxycycline or dexamethasone.

[0510] Example 337 The method of example 331, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

[0511] Example 338. The method of any one of Examples 331-337, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the brain of the subject, prevents and / or reduces expression and / or accumulation of β-amyloid protein in the brain of the subject, reduces inflammation, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents or reduces neuronal dysfunction / injury and / or death, prevents or reduces blood-brain barrier dysregulation and / or increases permeability, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

[0512] Example 339. The method of any one of Examples 331-338, wherein the therapy is provided in a first dosage amount that is less than a second dosage amount provided in the absence of the device.

[0513] Example 340. The method of any one of Examples 331-339, wherein the therapy is provided at a first dosing regimen that is less than a second dosing regimen that is provided in the absence of the device.

[0514] Example 341. The method of any one of examples 331-340, wherein the therapy is provided via a first route that is different from a second route that is provided in the absence of the device.

[0515] Example 342. The method of any one of Examples 331-341, wherein said therapy is provided by administering said therapy to said subject in need of said therapy.

[0516] Example 343. The method of any one of examples 331-342, wherein step (b) is performed after step (a) and before step (c).

[0517] Example 344. The method of any one of examples 331 to 343, wherein step (c) is performed after step (a) and before step (b).

[0518] Example 345. The method of any one of Examples 331 to 344, wherein the condition is neurodegeneration.

[0519] Example 346. The method of Example 345, wherein the neurodegeneration further comprises Alzheimer's disease, dementia, and / or cognitive impairment.

[0520] Example 347. The method according to any one of Examples 331 to 346, wherein the inner and / or outer surface has a generally cylindrical shape or a longitudinally undulating shape.

[0521] Example 348. The method of any one of Examples 331 to 347, wherein the device has a low-profile state and an expanded state, and when in the expanded state, the sidewall is generally tubular.

[0522] Example 349. A method according to any one of Examples 331 to 348, wherein the mitigating substance is configured to expand in response to an increase in blood pressure / pulse pressure or an increase in pulse wave intensity / FCWI in the blood vessel, and to relax as the blood pressure / pulse pressure or the increase in pulse wave intensity / FCWI in the blood vessel subsequently decreases.

[0523] Additionally, the following prophetic examples are illustrative of some embodiments of the present technology.

[0524] S. Example 350: Clinical Trial Design (Prophetic Example) The implantable device is placed in, near, around, in, or instead of at least a portion of the artery of the subject according to the present technology. After the implantable device is placed, the subjects who received the implantable device are randomized into one of at least two groups (group A: placebo and group B: therapeutic agent). The placebo is an experimentally appropriate placebo that is useful for distinguishing any specific effect of a drug, such as a pharmacologic acceptable carrier for the active ingredient in the therapeutic agent. The dose of the placebo corresponds to the amount of pharmacologic acceptable carrier that the subjects of group B receive. Group B can include two or more subgroups, and subjects are randomly assigned to each subgroup. Each of the subjects of these group B subgroups ultimately receives the same therapeutic agent, but the dose, route of administration, dosing regimen, or other parameters related to the treatment protocol can be changed.

[0525] T. Example 351: Clinical Trial Design (Prophetic Example) The therapeutic agent is delivered to the subject at a pre-specified dose, route of administration, frequency, and duration. After the therapeutic agent is delivered to the subject, the subject is randomized into one of at least two groups (group A: sham and group B: implantable device). For the subjects of group B, an implantable device is placed in, near, around, in, or in place of at least a portion of the subject's artery according to the present technology. The sham treatment of group A includes a delivery method related to the delivery of the implantable device used for group B, but does not deliver the implantable device to the subjects of group A.

[0526] In an alternative study, subjects are randomized into one of at least two groups (Group A: sham and Group B: implantable device). For subjects in Group B, an implantable device is placed in, near, around, in, or instead of at least a portion of the subject's artery according to the present technology. The sham treatment of Group A includes a delivery method related to the delivery of the implantable device used in Group B, but does not deliver the implantable device to the subjects in Group A. After Groups A and B are selected and provided with an implantable device (Group B) or sham treatment (Group A), the therapeutic agent is delivered to the subject at a pre-specified dose, route of administration, frequency, and duration.

[0527] In another alternative study, subjects are randomized into one of at least two groups (Group A: sham and Group B: implanted device). For subjects in Group B, an implanted device is placed in, near, around, in, or in place of at least a portion of the subject's artery according to the present technology, and a therapeutic agent is delivered to the subject at the time of implantation at a pre-specified dose, route of administration, frequency, and duration. The sham treatment of Group A includes a delivery method related to the delivery of the implanted device used for Group B, but does not deliver the implanted device to the subjects in Group A. Group A is also delivered with a therapeutic agent at the time of sham treatment at a pre-specified dose, route of administration, frequency, and duration.

[0528] U. Example 352: Drug-Based Therapy Research (Prophetic Example) Impact of reduced pulsatility on drug-based therapy: Immortalized human brain microvascular endothelial cells, such as HCMEC-SV40 cells, are cultured and cyclically stretched to approximately 15% as described in Gangoda et al., 2018. After cyclically stretching the brain endothelial cells, note confluence and collect samples of conditioned media. Reduce half of the brain endothelial cell cultures to approximately 5% stretch, while leaving the other half at 15% stretch. This represents with and without application of the device described herein, respectively.

[0529] Next, a drug (MMP inhibitor, (e.g., dexamethasone, doxycycline), an S1P modulator (e.g., fingolimod), or combination therapy with a senolytic therapy (e.g., D+Q) is administered as follows:

[0530] (I) Brain endothelial cells reduced to 5% stretch + drug

[0531] (II) Brain endothelial cells maintained at 15% stretch + drug

[0532] At predetermined time points after dosing, the following assays are performed for each condition.

[0533] (I) Conditioned media is collected and ELISA is used to measure expression of relevant biomarkers such as MMPs, S1P receptors, inflammatory cytokines, and amyloid pathway proteins (normalized to confluence).

[0534] (II) Cell viability may be quantified using an LDH assay.

[0535] (III) Western blots of brain microvascular endothelial cells are used to quantify the cellular content of inflammatory and amyloid pathway proteins.

[0536] V. Example 353: In vivo Surgically Induced Animal Model Study Design (Prophetic Example) In vivo model of the device. Male WT mice (e.g., C57Bl / 6 and BALB / c) and / or Alzheimer's disease model mice are acclimated for 2 weeks prior to the experiment. Animals are maintained under standard conditions of room temperature of 21-23°C, relative humidity of 30-70%, and a 12:12 hour light:dark cycle. Chow and water are available ad libitum.

[0537] After 2 weeks of acclimation, mice are weighed (every week throughout the study). Right and left carotid artery blood flow and pulse pressure are measured using any standard method in the art, such as a non-invasive Doppler Flow Velocity System (Scintica Instrumentation, Inc.) or an invasive pressure catheter (Millar). Mice are then divided into groups with comparable average body weights. Mice undergo transverse aortic constriction (TAC) surgery, which involves placing a constriction around the transverse aorta, restricting left ventricular (LV) outflow, thus creating a pressure load in the LV and inducing elevated pulse pressure. TAC surgery is performed using either (i) nylon sutures to induce a sustained (or permanent) elevation in pulse pressure, or (ii) absorbable sutures (e.g., polyglactin 910, which lasts for 14-21 days at maximum strength) to induce a transient (or temporary) elevation in pulse pressure, which gradually disappears as the suture dissolves, representing a reduction in the pulse pressure elevation and associated cerebral microbleeds that occur over time. Confirm the specific absorption rate of the selected absorbable suture and its effect on pulse pressure over time in mice. TAC mice receiving absorbable sutures model the attenuation device.

[0538] Next, the following groups of mice were tested to confirm that lower Alzheimer's-related pathology / higher blood brain barrier (BBB) ​​integrity was seen in the absorbable suture mice compared to the nylon suture TAC mice, supporting the mechanism of action of the attenuation device (reducing pulse pressure elevation):

[0539] (I) WT mouse, TAC using nylon suture

[0540] (II) WT mice, TAC using absorbable sutures and / or

[0541] (III) Alzheimer's mouse, TAC using nylon suture

[0542] (IV) Alzheimer's mouse, TAC using absorbable suture

[0543] The time point for group comparison after TAC surgery may be determined based on when optimal contrast pulse pressure is achieved using nylon sutures versus absorbable sutures. In certain embodiments, the starting point of the experiment may be approximately 6 weeks after TAC.

[0544] At the time points for group comparison, mice are weighed and blood flow and pulse pressure are recorded. Mice are then injected with Evans Blue dye (excitation 470 / 540 nm, emission 680 nm) or any other fluorescent tracer known in the art, perfused, and then sacrificed. Whole brains are extracted and brain tissue is immediately fixed (or snap frozen depending on what the tissue is to be used for) and sectioned. Mouse hearts may be harvested and weighed. Fixed ipsilateral and contralateral histological brain sections are stained with Prussian blue to quantify microhemorrhages as described in Supplement 1 of Montgolfier et al. (see above) or confocal imaged for fluorescence distribution. Immunohistochemistry or qPCR to measure expression of BBB markers such as tight junction proteins may also be considered as an indicator of BBB integrity. MMP (a marker of increased BBB permeability) and NF-kB (an inflammatory marker associated with Alzheimer's disease) protein expression can also be measured in brain microvessels and brain tissue. Amyloid beta deposits in neural tissue can also be quantified in Alzheimer's disease model mice. Finally, immunohistochemistry for fibrin in brain sections can be performed to visualize clotting of blood components that have leaked through the BBB into the neuropil.

[0545] In vivo models of combination therapy. Following successful completion of the proof-of-concept experiments described above, the benefit of reducing pulse pressure elevation on the efficacy of drug or cell therapy is studied in vivo. First, WT or Alzheimer's disease model mice are subjected to TAC surgery using either nylon or absorbable sutures as previously described.

[0546] At the time points for group comparison after TAC surgery as described above, mice are administered (intracarotid artery or via tail vein) fluorescently labeled stem / progenitor cells or drugs as described herein (e.g., "therapeutic agents," "drugs," "therapy," EDG receptor family modulators, MMP inhibitors, senolytic agents, and / or combinations thereof).

[0547] For example, mice may be administered a therapeutic agent (an MMP inhibitor (e.g., dexamethasone, doxycycline), an S1P modulator (e.g., fingolimod), or a senolytic therapy (e.g., D+Q) as described below.

[0548] (I) TAC using nylon suture + therapeutic agent

[0549] (II) TAC using absorbable sutures + therapeutic agent

[0550] Exemplary therapies that can be tested according to this example include, but are not limited to, fingolimod, dexamethasone, and doxycycline.

[0551] At time points for group comparison, mice are weighed and blood flow and pulse pressure are recorded. Mice are then injected with Evans Blue dye / fluorescent tracer, perfused, and then sacrificed. Whole brains are extracted and brain tissue is immediately fixed (or snap frozen depending on what the tissue is to be used for) and sectioned. Mouse hearts are harvested and weighed. Fixed ipsilateral and contralateral histological brain sections are stained with Prussian Blue to quantify microhemorrhages (see Supplement 1 of Montgolfier et al., supra) or confocal imaged for fluorescence distribution. PKH26 / CFDA-SE (fluorescent) signal can reveal the abundance of fluorescently labeled stem or progenitor cells recruited to the brain microvasculature. Evans Blue / fluorescent tracer signal can indicate BBB leakage. Immunohistochemistry or qPCR to measure the expression of BBB markers such as tight junction proteins can also be considered as an indicator of BBB integrity. MMP (a marker of increased BBB permeability) and NF-kB (an inflammatory marker associated with Alzheimer's disease and stem cell dysfunction) protein expression can also be measured in brain tissue. Finally, immunohistochemistry for fibrin in brain sections can be performed to visualize clotting of blood components that have leaked through the BBB into the neuropil.

[0552] The in vivo model described herein can be used to test any therapy administered in combination with the reduction of pulse pressure rise (the effect of attenuating device), including the therapies discussed herein. These combined therapy experiments will confirm whether absorbable suture TAC mice + therapeutic agent show less BBB disruption than nylon suture TAC mice + therapeutic agent. If so, this supports the possibility that the device synergistically enhances the effectiveness of such therapeutic agent.

[0553] W. Example 354: In Vivo Chemically Induced Pulse Pressure Study Design (Prophetic Example) As an alternative to the TAC surgically induced model of elevated pulse pressure described above, a chemically induced animal model of elevated pulse pressure can also be used to test the biological therapeutics described herein (e.g., "therapeutic agents," "drugs," "therapy," EDG receptor family modulators, MMP inhibitors, and / or senolytic agents, or combinations thereof). Such a model can be generated by treating animals (e.g., rats) with warfarin / vitamin K1 (WVK) according to Essalihi et al., A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K1 treatment, Am J Hypertens. 2003 Feb;16(2):103-10 (doi:10.1016 / s0895-7061(02)03204-1). WVK treatment induces isolated systolic hypertension and thus elevated pulse pressure. This pulse pressure increase can be reduced by subsequent treatment with darusentan (DAR) and / or acetazolamide (ACTZ) treatment according to Essalihi et al., Regression of medial elastocalcinosis in rat aorta: a new vascular function for carbonic anhydrase, Circulation. 2005 Sep 13;112(11):1628-35 (doi:10.1161 / CIRCULATIONAHA.104.528984).

[0554] To compare cerebrovascularly healthy animals that experience elevated pulse pressure compared to those that experience reduced pulse pressure, animals are treated with one or more of the following groups: [Table 7]

[0555] Following the treatment period, cognition, microhemorrhage, BBB permeability, neuroinflammation, neurodegeneration, and BBB tight junction expression can be quantified and compared for each group of rats as detailed in the table above.

[0556] The study design described herein can be used to test any therapy intended to be administered in combination with reducing pulse pressure elevation (the effect of an attenuation device), including the therapies described herein. Exemplary therapeutic treatments that can be tested using this study design include, but are not limited to, fingolimod, dexamethasone, and doxycycline.

[0557] X. Example 355: Fingolimod can improve BBB function in the presence of persistently high pulse pressure. This study was conducted to investigate a "combination" approach to protect the blood-brain barrier (BBB) ​​by (i) a drug approach, in this case fingolimod, and (ii) an experimental approach to mimic the effects of a device designed to reduce cerebral pulse pressure. Here, the experimental approach was the application of an absorbable suture to the ascending aorta between the right and left common carotid arteries (TAC procedure). While a permanent TAC would generate a high pulse pressure in the right cerebral hemisphere, a temporary TAC (absorbable suture) should mimic a period of high pulse pressure followed by normal pulse pressure once the suture is absorbed, similar to what should be obtained with an external carotid device as described in the embodiments herein.

[0558] Here, we used absorbable TAC sutures that were stated by the manufacturer to be absorbed after 7–10 days, but absorption did not occur in all but one mouse, as discussed below. However, as a useful "proof of concept" experiment for a combined drug-device approach, this experiment still provided us with the opportunity to test whether fingolimod improved BBB function in the presence of persistently high pulse pressure.

[0559] Study design. Sixty mice were evenly divided into two groups: a permanent TAC group receiving simple sutures and a temporary TAC group receiving absorbable sutures. As shown in FIG. 26, the protocol calls for treating all mice with fingolimod starting from day 12 after TAC surgery. Deviations from this protocol are discussed below.

[0560] Mortality after TAC. The mortality rate of mice in the permanent TAC group (7.4%) was higher than that in the temporary TAC group (33.3%). The absorbable sutures were not very stiff, and several surgeries were required to adjust the tension applied to the sutures.

[0561] Weight Tracking After TAC As shown in Figure 21 and Tables 2-3 below, TAC surgery using absorbable sutures was associated with higher weight loss.

[0562] [Table 2]

[0563] [Table 3]

[0564] Echocardiogram data. Echocardiograms assessing peak velocity were performed before (-3 days) and after TAC surgery (4, 6, 9, 12, 15, and 42 days) to detect whether the suture was absorbed. As shown in Figure 22A-B and Table 4 (below), peak velocity (Peak V) was decreased in only one mouse, suggesting that the suture was completely absorbed at the end of TAC in that particular mouse (mouse number 20, 20A in the absorbable group).

[0565] [Table 4]

[0566] LV: left ventricle, LVAWd: left ventricular anterior wall thickness at end diastole, LVPWd: left ventricular posterior wall thickness at end diastole, LVEDd: left ventricular end diastolic diameter, LVEDs: left ventricular end systolic diameter, FS: fractional shortening, LVVd: left ventricular end diastolic volume, LVVs: left ventricular end systolic volume, EF: ejection fraction. Data are means ± standard error of the mean from n mice. Two-way ANOVA (TAC × suture), followed by Sidak's multiple comparison test. (†: p<0.05 compared to basal condition = effect of TAC, * : p<0.05 compared with absorbable sutures = effect of suture type).

[0567] The use of absorbable sutures results in higher variability in echocardiographic parameters and a tendency towards a greater effect of TAC on cardiac characteristics (except for the mean gradient).

[0568] Millar data, 6 weeks after TAC. Millar was performed on untreated and treated mice (fingolimod, 0.3 mg / kg / day, last 2 weeks of TAC) on the day of sacrifice. Carotid artery pressure and left ventricular pressure parameters are shown in Tables 5-6 below.

[0569] [Table 5]

[0570] Data are means ± standard error of the mean for n mice. Two-way ANOVA (suture × treatment) followed by Sidak's multiple comparison test.

[0571] [Table 6]

[0572] Data are means ± standard error of the mean for n mice. Two-way ANOVA (suture × treatment) followed by Sidak's multiple comparison test.

[0573] Cognition (Y-maze - exploratory behavior) Cognition was measured according to the number of behavioral changes in the three arms of the Y-maze, as shown in Figures 23-24.

[0574] Evans Blue Data. Analysis of the above in vivo data demonstrates that the absorbable suture was not absorbed in time, i.e., within 7-10 days as advertised by the manufacturer, Ethicon, except for mouse 20A. As a result, there was no statistical difference between these two groups (simple suture and absorbable suture). The same was true for the other two fingolimod-treated groups. Nevertheless, mice were treated for the last 2 weeks (starting 4 weeks after TAC surgery) despite the lack of evidence of normalization of aortic diameter based on repeated echo assessments, as discussed below.

[0575] Twenty-three mice were treated with fingolimod (0.01 mg / day in drinking water, i.e., 0.3 mg / kg / day) for the last 2 weeks, i.e., 4 weeks after TAC surgery. In the initial protocol, it was planned to treat the mice after resorption of the sutures, estimated at 12 days after surgery, and thus for 4.5 weeks. Because resorption of the sutures had not occurred, it was decided to treat the mice for the last 2 weeks, even when the injury was expected to be well established.

[0576] Images were reconstructed to acquire the entire right hemisphere and Evans Blue extravasation was quantified. The analysis was performed by a blinded technician using Image J® and background fluorescence filters. Four mice were not treated (23A, 24A, 30A, 40A) and three mice were treated (41A, 42A, 52A). Figure 26A represents the entire data acquisition, after which the Evans Blue data was tested for normality and log-normality as shown in Figure 26B.

[0577] Using computer-generated exclusion of outlier distributions of individual data for each region of interest (ROI) from individual mice, the dot plots shown in Figure 27 suggest that fingolimod somewhat protects cerebrovascular endothelial integrity by preserving endothelial barrier function. However, when all values ​​from individual mice are averaged without exclusion of outlier distributions, this trend remains, but statistical significance is lost due to the small number of animals included in each group (including outliers) and the large variability in Evans blue diffusion.

[0578] All mice from the two groups (treated and untreated) had the same velocity peak (a surrogate for pulse pressure) measured by echocardiography (see Figures 29A-B), therefore, the potential beneficial effect of treatment cannot be attributed to lower pulse pressure in the brain.

[0579] In summary, S1P 1 The receptor ligands are likely protective by preventing the increased BBB permeability associated with elevated cerebrovascular pulse pressure. Additional studies may be performed on larger cohorts of mice with normalized cerebrovascular pulse pressure after suture absorption. Treatment should be initiated just one week after elevated pulse pressure, concomitant with normalization of pulse pressure, to maximize efficacy.

[0580] qPCR analysis. Target mRNA expression was performed in the brain microvessel fraction. Two approaches were followed: quantification (RT-qPCR) was performed in the whole brain microvessel fraction (untreated or treated, n=5 per group, unpaired t-test) or after isolation of the ipsilateral and contralateral hemispheres of the brain of three treated or untreated mice (paired statistical analysis (comparison of left vs. right) and unpaired t-test (comparison of no TT vs. TT)). Target gene transcripts are discussed below.

[0581] S1P1 (see Figures 30A-B): A G protein-coupled receptor that is highly expressed in endothelial cells. It binds with high affinity and specificity to the ligand sphingosine-1-phosphate and has been suggested to be involved in processes regulating endothelial cell differentiation. Activation of this receptor induces cell-cell adhesion.

[0582] S1P3 (see Figures 31A-B): This gene encodes a member of the EDG family of receptors that are G protein-coupled receptors. This protein has been identified as a functional receptor for sphingosine 1-phosphate and likely contributes to the regulation of angiogenesis and vascular endothelial cell function.

[0583] B2M (see Figures 32A-32B): Also known as B2M 2 Microglobulins are components of MHC class I molecules, which are the α 1 , α 2 , and α 3 Has protein.

[0584] CERS4 (see Figures 33A-B): Ceramide synthase that catalyzes the formation of ceramide from sphinganine and acyl-CoA substrates with high selectivity for long-chain and very long-chain (C18:0 to C22:0) acyl donors.

[0585] CERS2 (see Figures 34A-B): Plays a non-redundant role in the synthesis of ceramides with very long chain fatty acids in the kidney, liver, and brain.

[0586] Claudins (see Figures 35A-B): Claudins function as major components of the tight junction complexes that regulate epithelial permeability.

[0587] ICAM-1 (see Figures 36A-B): Intercellular adhesion molecule 1. ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L / beta-2). During transendothelial migration of leukocytes, ICAM1 engagement promotes assembly of the endothelial apical cup.

[0588] VCAM-1 (see Figures 37A-B): Vascular cell adhesion molecule 1. Important in cell-cell recognition. Appears to function in leukocyte-endothelial cell adhesion. Interacts with integrin alpha-4 / beta-1 (ITGA4 / integrin beta-1, ITGB1) on leukocytes and mediates both adhesion and signaling.

[0589] MMP9 (see Figures 38A-B): A matrix metalloproteinase that plays an essential role in localized proteolysis of the extracellular matrix and leukocyte migration. It cleaves collagen types IV and V into a large C-terminal three-quarter fragment and a shorter N-terminal one-quarter fragment. It degrades fibronectin but not laminin or Pz peptides.

[0590] Cyclophilin-A (CYPA), also known as peptidylprolyl isomerase A (PPIA), is used as a housekeeping gene and is highly abundant and found in the cytosol.

[0591] S1P 1Receptor ligands have mixed effects on cerebral microcirculation. They tend to decrease S1PR1 and S1PR3 mRNA expression in the ipsilateral hemisphere and globally, respectively, which may represent downregulation of the receptors in response to chronic exposure to the agonist. Globally, CERS2 is decreased, while CERS4 expression is decreased in the treated ipsilateral hemisphere, again likely related to downregulation of processing and synthesis pathways. What is more difficult to explain is the following: Claudin-5 expression is significantly decreased globally by treatment, suggesting a decrease in tight junctions between cells. The effect of treatment on MMP-9 is unclear, tending to increase in the contralateral hemisphere, while ICAM-1 is decreased by treatment in the ipsilateral hemisphere, with a similar trend in VCAM-1 expression. Immunofluorescence staining of the brain should provide evidence that the treatment protected the ipsilateral hemisphere from capillary rarefaction caused by acute and prolonged elevation of pulse pressure.

[0592] Consideration

[0593] Under conditions of high pulse pressure, fingolimod appeared to protect the blood-brain barrier from excessive permeability. Certain cellular analyses (e.g., cellular analyses of cell adhesion molecules) supported the possible benefit of this drug in this context. Further experiments can be performed using optimized "transient TAC" conditions and a larger number of mice. Taken together, the data encourage a combined approach to BBB protection.

[0594] VIII. Conclusion Although many of the embodiments are described above with respect to systems, devices, and methods for treating and / or slowing the progression of vascular and / or age-related neurological conditions (e.g., dementia) with combination therapeutic agents (e.g., drugs) and endovascular methods, the technology is applicable to other applications and / or other approaches, such as surgical implantation of one or more attenuation devices in combination with one or more drugs and / or treatment of blood vessels other than arterial blood vessels that supply blood to the brain, such as the abdominal aorta. For example, any suitable site within a blood vessel may be treated, including the ascending aorta, the aortic arch, the brachiocephalic artery, the right subclavian artery, the left subclavian artery, the left common carotid artery, the right common carotid artery, the internal carotid artery, and the external carotid artery, and / or branches of any of the foregoing. Furthermore, in addition to the embodiments described herein, other embodiments fall within the scope of the technology. Additionally, some other embodiments of the technology may have configurations, components, or procedures that differ from those described herein. Thus, those skilled in the art will accordingly appreciate that the present technology may have other embodiments having additional elements or that the present technology may have other embodiments that do not have some of the features shown and described above with reference to Figures 2A-20.

[0595] The above detailed description of the embodiments of the present technology is not intended to be exhaustive or to limit the present technology to the precise form disclosed above. Where the context permits, singular or plural terms may also include the plural or singular terms, respectively. Although specific embodiments of the technology and examples of the technology have been described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the art will recognize. For example, while steps are presented in a given order, alternative embodiments may perform the steps in a different order. Various embodiments described herein may also be combined to provide further embodiments.

[0596] Further, unless the word "or" is expressly limited to mean only a single item in relation to a list of two or more items, the use of "or" in such a list should be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. In addition, the term "comprising" is used throughout to mean including at least the recited features, but not to exclude any more of the same features and / or other features of additional types. Although specific embodiments have been described herein for purposes of illustration, it will also be understood that various modifications can be made without departing from the technology. Furthermore, although advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may exhibit such advantages, and not all embodiments necessarily need to exhibit such advantages to fall within the scope of the technology. Thus, the present disclosure and related technology can encompass other embodiments not expressly shown or described herein.

Claims

1. A system for use in treating and / or preventing one or more effects of neurodegeneration in a subject in need thereof, comprising: an effective amount of a therapy for use in treating and / or preventing one or more effects of said neurodegeneration; a device for use in treating and / or preventing one or more effects of said neurodegeneration; the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; The system, wherein the therapy is an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof.

2. The system described in claim 1, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

3. The system described in claim 1, wherein the MMP inhibitor is doxycycline or dexamethasone.

4. The system described in claim 1, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

5. The system of claim 1, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and / or reduces expression and / or accumulation of beta-amyloid protein in the subject's brain, reduces inflammation, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents neuronal dysregulation / damage and / or death, prevents blood-brain barrier dysregulation and / or damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

6. A system described in any one of claims 1 to 5, wherein the therapy is provided at a first dosage that is less than a second dosage that would be provided in the absence of the device.

7. The system described in claim 1, wherein the neurodegeneration further includes Alzheimer's disease, dementia, and / or cognitive impairment.

8. A system for use in treating and / or preventing one or more effects of neurodegeneration in a subject in need thereof, comprising: an effective amount of a therapy for use in treating and / or preventing one or more effects of said neurodegeneration, said therapy being an EDG receptor family modulator, an MMP inhibitor, or a senolytic agent, or a combination thereof; a device for use in treating and / or preventing one or more effects of said neurodegeneration; the device comprising: a flexible damping member forming a generally tubular structure having an inner surface and an outer surface, the inner surface being formed from a sidewall having one or more at least partially deformable portions configured to move longitudinally and / or radially within the one or more at least partially deformable portions in response to pulsatile blood flow within the blood vessel; a mitigation material disposed within the one or more at least partially deformable portions of the sidewall, the mitigation material being configured to move longitudinally and / or radially within a partially deformable portion in response to pulsatile blood flow within the blood vessel; the effective amount of the therapy for treating and / or preventing one or more effects of the neurodegeneration is carried by one or more of the at least partially deformable portions of the device; When the one or more at least partially deformable portions are at least partially deformed, the effective amount of a therapy for treating and / or preventing one or more effects of neurodegeneration is released from the device.

9. The system described in claim 8, wherein the effective amount of the therapy further comprises a first effective amount of the therapy and a second effective amount of the therapy.

10. The system described in claim 8, wherein the EDG receptor family modulator is an S1P receptor agonist selected from fingolimod, siponimod, ozanimod, or ponesimod.

11. The system described in claim 8, wherein the MMP inhibitor is doxycycline or dexamethasone.

12. The system described in claim 8, wherein the senolytic agent is dasatinib, quercetin, or a combination of dasatinib and quercetin.

13. The system of claim 8, wherein the therapy prevents and / or reduces abnormal cleavage of amyloid precursor protein in the subject's brain, prevents and / or reduces expression and / or accumulation of beta-amyloid protein in the subject's brain, reduces inflammation, reduces and / or prevents oxidative stress, reduces and / or prevents ischemia, prevents neuronal dysregulation / damage and / or death, prevents blood-brain barrier dysregulation and / or damage, eliminates senescent cells, improves tight junctions, inhibits MMPs, and / or induces transcriptional activation of TIMPs.

14. A system described in any one of claims 8 to 13, wherein the therapy is provided at a first dosage that is less than a second dosage that would be provided in the absence of the device.

15. The system described in claim 8, wherein the neurodegeneration further includes Alzheimer's disease, dementia, and / or cognitive impairment.

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